Next Article in Journal
Impact of the COVID-19 Pandemic on Staging Oncologic PET/CT Imaging and Patient Outcome in a Public Healthcare Context: Overview and Follow Up of the First Two Years of the Pandemic
Next Article in Special Issue
Resection of Colorectal Liver Metastases with Major Vessel Involvement
Previous Article in Journal
Current Data and Future Perspectives on Patients with Atrial Fibrillation and Cancer
Previous Article in Special Issue
Clinical Outcomes of Upfront Primary Tumor Resection in Synchronous Unresectable Metastatic Colorectal Cancer
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 22
10.3390/cancers15225359
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Colorectal Liver Metastasis: Can Cytokines Make the Difference?

by
Costanza Ballarò
1,*,
Valeria Quaranta
2 and
Gianluigi Giannelli
3
1
Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
2
Laboratory of Personalized Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
3
Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(22), 5359; https://doi.org/10.3390/cancers15225359
Submission received: 8 September 2023 / Revised: 20 October 2023 / Accepted: 8 November 2023 / Published: 10 November 2023
(This article belongs to the Special Issue Colorectal Liver Metastasis (Volume II))
Browse Figures
Versions Notes

Abstract

:

Simple Summary

Colorectal cancer (CRC) is one of the most common malignancies worldwide, with a mortality rate of 86%. The main cause of death is the development of colorectal liver metastases (CRLMs). The communication between cancer cells and the environment is a prerequisite for generating a favorable tumor microenvironment, and it is mediated by soluble molecules such as cytokines, growth factors, and extracellular vesicles. Mounting evidence suggests that cytokines play a decisive role in CRC progression and metastasis. In this review, we highlight the involvement of different cytokines during the development of CRLMs and emphasize the complexity as well as therapeutic implications of the cytokine milieu.

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.

1. Introduction

Colorectal cancer (CRC) is one of the three most common malignancies and the third leading cause of cancer-related death worldwide [1]. Despite improvements in its diagnosis, screening, and treatment, the global mortality of CRC rose from 437,000 in 1990 to 915,000 million deaths in 2020 [2,3]. Additionally, the International Agency for Research on Cancer (IARC) estimates an increase from 1.9 million (data from 2020) to 3 million new cases of colon cancer by 2040 [4]. CRC metastasis remains a major problem after curative treatment and is the critical cause of CRC-related death. The liver is the organ most commonly affected by distant metastasis, mostly due to the portal vein system, which directly connects the colon–rectum and the liver [5]. Approximatively 50% of CRC patients present liver metastases at the time of the primary diagnosis or develop metastases within 5 years after the diagnosis [6]. Generally, colorectal liver metastasis (CRLM) has a poor prognosis and a survival rate of only 14–15% [7]. Surgical resection and chemotherapy are the only treatments that offer long-term survival for patients with CRLM. Nevertheless, only 10–20% of CRLM cases are suitable for resection at the time of diagnosis [7]. Currently, the direct blockading of immune checkpoints to inhibit immune escape is the most well-established immunotherapeutic approach for the treatment of several cancer types [8,9,10]. However, the response of CRC patients to immune checkpoint inhibitors (ICIs) is subject to genomic susceptibility. ICIs are more effective in patients with high DNA microsatellite instability (MSI) or deficient mismatch repair status (MMR) CRLM [11,12]. In contrast, ICIs alone or in combination show only weak outcomes in patients with microsatellite stability and/or mismatch repair proficient CRLM [13,14] Therefore, it is crucial that more effective strategies be developed both to prevent metastases spreading and to improve the survival of CRLM patients.
The tumor microenvironment (TME) is implicated in every aspect of tumor progression and metastasis, including the initial engraftment and growth. Moreover, the TME is known to be involved in regulating the response to immunotherapy, due to its ability to mediate a primary resistance or acquire resistance to cancer treatments [15]. As with most solid cancers, the CRC TME comprises not only tumor cells but also several other cell types, such as cancer-associated fibroblasts (CAFs), immune cells (e.g., macrophages, natural killer cells, dendritic cells, and T lymphocytes), and stromal cells [16]. The communication between different cell types contributes to determining the tumor fate. Cells communicate through direct cell interactions or soluble factors, such as cytokines, growth factors, extracellular vesicles (e.g., exosomes), and extracellular matrix (ECM) components. Among them, cytokines play a fundamental role in CRLM development, since their involvement in tumor initiation, invasion, and resistance to cancer treatments is well established (Table 1) [17]. Cytokines include chemokines, interferons, and interleukins, and act through cell surface receptors. Notably, it has been demonstrated that defects in cytokine signaling contribute to CRC progression and are often predictive of the worst disease evolution [18]. Recently, different studies have revealed that some cytokines enhance or inhibit the action of other cytokines in complex ways, suggesting the importance of delineating the impact of cytokine networks on carcinogenesis. In fact, due to their immunosuppressive role and, in some cases, their overlapping functions, cytokines can be considered therapeutic targets, and their inhibition may sensitize many tumors to ICIs or other immunotherapies, thus improving therapeutic outcomes. In this review we highlight how cytokine networks influence CRLM development and, therefore, the potential employment of cytokine-based therapies.

2. Mechanism of Colorectal Liver Metastasis Development: Different Phases, Common Cytokines

The dissemination of primary tumor cells to a specific organ is undoubtedly facilitated by anatomical factors, such as the blood flow pattern. The hepatic artery and portal venous circulation can partly explain why the liver is the preferential organ for metastatic spread, but this is not sufficient to explain the metastasis formation. Indeed, according to Steven Paget’s hypothesis, circulating cancer cells must also find a suitable microenvironment in order to colonize an organ [61]. The liver microenvironment represents a unique metastatic site for CRC circulating cells’ engraftment, survival, and growth, and several factors contribute to its composition. Among them, it is necessary remember that the liver is continuously exposed to intestinal antigens, which create an immunotolerant environment that favors CRLM [62]. Additionally, it has been shown that liver diseases such as non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) might also improve the suitable conditions for CRLM [63,64]. Moreover, resident liver cells themselves secrete many cytokines and chemokines responsible for liver-specific colonization [65]. For example, a high expression of the chemokine CXCL12 in the liver parenchyma mediates the recruitment of CRC cells that express high levels of its receptor, CXCR4, thus contributing to hepatic metastasis [66]. Furthermore, the CCL20-CCR6 pathway plays an important role in the signaling cascade associated with the metastatic spread of CRC to the liver [67].
By analyzing genomic data, it has recently been demonstrated that the genetic difference between primary CRC cells and distant metastases in the liver and brain is small, suggesting that metastatic spread is an early event in tumorigenesis [68,69].
The pathogenic development of CRLM is facilitated by two critical niches, namely the pre-metastatic niche and post-tumor invasion niche. The former is driven by factors secreted by the primary tumor that, in turn, recruit non-parenchymal cells, including Kupffer cells (KCs, resident liver macrophages), hepatic stellate cells (HepSCs, pericytes in the perisinusoidal space of the liver), myeloid-derived suppressor cells (MDSCs, immune cells from the myeloid lineage), and neutrophils. The latter, instead, develops following tumor cells’ entry into the liver, and proceeds through different phases. These include (1) a microvascular phase, when cancer cells infiltrate and become trapped in liver vessels; (2) an extravasion and pre-angiogenic phase, when invading tumor cells relocate in the liver and collaborate with stromal cells to form a supportive TME; (3) an angiogenic phase that leads to the formation of intra-metastatic vessels; and (4) a growth phase, where metastatic cells acquire an adequate blood supply and proliferate rapidly to form a detectable tumor (Figure 1). It has been demonstrated that cytokine-mediated signaling networks affect each phase of CRC progression in several ways [17] (Figure 2).

2.1. EMT

The epithelial–mesenchymal transition (EMT) is a process that occurs when epithelial cells lose their characteristics (cell polarity, cell–cell adhesion, and cell–matrix adhesion) and acquire a mesenchymal phenotype [70], thereby gaining migratory and invasive properties. Transcription factors such as SNAIL, TWIST, and ZEB repress the expression of adhesion molecule E-cadherin in favor of increased levels of the mesenchymal adhesion molecule N-cadherin, thus suppressing the cancer cells’ epithelial phenotype and activating the mesenchymal phenotype. Intriguingly, it has been demonstrated that in CRC cells the expression of these transcription factors is often upregulated [71,72].
Different cytokines play a fundamental role in the EMT. Tumor necrosis factor α (TNFα) is a key inflammatory cytokine produced by both hematopoietic and non-hematopoietic cells. Intestinal epithelial cells are highly sensitive to TNFα due to high levels of expression of its receptor, TNFR1, which potently activates NF-kB oncogenic pathways [51,52]. TNFα is involved in the EMT through increasing the activity of SNAI1, an effect mediated by AKT-dependent GSK-3β inactivation [73]. Finally, TNFα is also involved in CRC cells’ migration through upregulating TROP-2, a transmembrane glycoprotein strongly associated with tumor invasion and metastasis [74]. Interleukin-1β (IL-1β) is a cytokine expressed at high levels in several cancer types, and its expression increases during the progression of CRC. IL-1β has been found to promote the EMT phenotype in colon cancer cells through ZEB1 upregulation, since Zeb1 knockdown cells display the reversal of the IL-1β-induced EMT [26]. Moreover, neutralization experiments using anti-IL-1β-specific antibodies showed that IL-1β is sufficient to activate Wnt signaling through the inhibition of GSK-3β, thereby inducing mesenchymal characteristics [27].
IL-6 is a crucial mediator of inflammation and immunity produced by diverse cell types (e.g., T cells, macrophages, and CRC cells). It has several important roles in CRC progression, including triggering the EMT via JAK2/STAT3 signaling [31]. STAT3 activation upregulates CEACAM 5, which plays a pivotal role in cell adhesion, migration, and metastasis in CRC [75]. Recent studies have demonstrated that NOTCH signaling contributes to CRC pathogenesis due to its role in the EMT induction [76]. Intriguingly, supernatants from human colon cancer mesenchymal stem cells enhance the invasive activity of CRC cells in vitro [77]. Notably, IL-6 is induced by various factors, such as TNFα and NF-kB [53]. IL-11, a member of the IL-6 family, is highly expressed in human CRC and is also a stronger STAT3-activating cytokine than IL-6 [43]. Genetic variation in the genes encoding IL-8 and its receptor CXCR2 has been unveiled as another important modulator of tumorigenesis, being associated with CRC progression, therapeutic resistance, and tumor recurrence [37]. Accordingly, the transgenic expression of IL-8 in mouse skin promotes the outgrowth and metastasis of subcutaneous CRC xenografts [38]. Conversely, the EMT- inducing transcription factor SNAI1 can induce IL-8 expression in CD44+ cancer stem-like cells, and both are co-expressed in human CRC [78]. Recently, GDF15, a member of the transforming growth factor β (TGFβ) superfamily, has been characterized as a biomarker for screening early stage CRC, and its expression is correlated with liver metastasis and poor survival [79]. Consistent with this, an expression analysis performed on human gastric tumor tissues showed a high expression of GDF15 in gastric cancer cells, correlated with invasive potential. Moreover, the overexpression of GDF15 in a human gastric cell line increases both the activity of urokinase-type plasminogen activator and the expression of its receptor, parameters associated with tumor invasiveness. TGFβ is a multifaced cytokine that exhibits a double role in CRC. In early stage cancer it acts as a tumor suppressor by inducing cell cycle arrest and apoptosis, while in late-stage cancer it promotes tumorigenesis, being the central activator of the EMT [80]. TGFβ induces the SMAD pathway (the canonical pathway) and non-SMAD signaling pathways (non-canonical pathways, such as MAPK and PI3K) to control multiple processes in carcinogenesis [81]. For example, TGFβ can induce the secretion of IL-11 by CAFs, which triggers STAT3 signaling in CRC and confers a high metastatic capacity to them [44]. In addition, it has been shown that TNFα accelerates the TGFβ-induced EMT, and this process depends on enhanced p38 MAPK activity [54]. FLH2 is an important adaptor and modifier in protein interactions, and is highly expressed in primary and metastatic colon cancer cells [49]. It acts as a potent inducer of the EMT by stimulating vimentin as well as matrix metalloproteinases-9 (MMP-9) and inhibiting E-cadherin expression. Nevertheless, it has been demonstrated that FHL2 expression is stimulated by TGFβ in a SMAD-independent manner [49]. An in vivo study reported that elevated levels of TGFβ in adjacent stromal cells increase liver metastasis formation by CRC cells [44], while the inhibition of stromal TGFβ signaling was found to block liver metastasis initiation in vivo and suppress angiogenesis in vitro [82,83]. All of this evidence suggests that TGFβ provides a continuous stimulus that promotes metastasis in CRC.

2.2. Microvascular Phase

When CRC cells undergo the EMT they can invade surrounding tissues, intravasate into the blood, and pass through the portal venules into the liver capillaries, called sinusoids. Although the process of intravasation is still poorly understood, it is known that to facilitate circulating CRC cells’ invasion of the underlying tissue the initial steps require the disruption of the endothelial cell–cell junctions and the basement membrane, both processes mediated by MMPs secreted by CAFs, tumor cells, and tumor-associated macrophages (TAMs) [84]. TAMs are conventionally categorized as two subtypes, namely M1 and M2. M1 macrophages are mainly involved in proinflammatory responses and have antitumor effects, while the M2 subtype has anti-inflammatory effects and promotes tumor growth. In particular, M2 macrophages are activated by several cytokines and are implicated in different protumoral activities, such as immunosuppression, invasiveness, and angiogenesis [32]. Interestingly, using a zebrafish model, it has been demonstrated that IL-6 or TNFα-activated M2 macrophages can physically interact with CRC cells, thus facilitating cancer cells’ intravasation and thus promoting tumor metastasis [32]. Tumor cells’ intravasation in the sinusoids triggers a rapid answer by the liver, which adopts several defense mechanisms in order to protect the organ and thereby the entire organism against disseminating CRC cells. KCs represent the first line of defense, since they can kill tumor cells via phagocytosis and by releasing proteinases as well as TNFs, both processes potentiated by natural killer (NK) cells [85]. The death of tumor cells and tissue damage lead to the release of various inflammatory interleukins, including IL-1, IL-6, IL-8, and IL-18, as well as chemokines such as CCL5 [39]. In turn, these cytokines can recruit more immune cells to enhance local tumor immunity. On the other hand, this local inflammatory response can also lead to the progression to the extravascular phase by upregulating the expression of adhesion molecules necessary for the extravasation [19]. Finally, a recent study demonstrated that KCs also have a prometastatic role. Indeed, KCs could be recruited by the TCF4-CCL2/CCR2 pathway, which is overexpressed in CRC, and be polarized into the M2 subtype, which can secrete protumor cytokines such as IL-4, IL-13, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) [25]. Furthermore, it has been shown that KCs and HepSCs are involved in immune surveillance escape through two mechanisms: by releasing the chemokine CXCL1, and thus inducing MDSC recruitment, and by secreting CCL5, thus inhibiting cytotoxic T cells’ function [17,85]. One way to circumvent death via phagocytosis derives from platelets: it has been demonstrated that platelets coat tumor cells to form a physical barrier that protects them against an immunological attack [25]. Furthermore, after binding CRC circulating cells, platelets secrete TGFβ and platelet-derived growth factor (PDGF), which maintain the EMT state of tumor cells and contribute to the immunosuppression of NK cells [86].

2.3. Extravascular and Pre-Angiogenic Phase

The fraction of CRC circulating cells that escape immune surveillance must adhere to the endothelium of sinusoids to extravasate and form a metastatic lesion. The liver sinusoidal endothelial cells (LSECs) form the lining of the hepatic sinusoids and they control the trafficking of molecules as well as cells between the blood and the liver. They express E-selectin, a cell adhesion molecule, itself induced by cytokines and involved in CRC cell adhesion to LSECs [87]. Under physiological conditions, LSECs express low levels of E-selectin. However, Khatib et al. showed that once CRC circulating cells intravasate, they activate KCs to produce TNFα and IL-1β. In turn, these cytokines induce the expression on LSECs of E-selectin and other adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [19]. These adhesion receptors mediate CRC cell adhesion onto endothelial cells, thus promoting trans-endothelial migration and, therefore, successful extravasation into the liver parenchyma [88].

2.3.1. Preparation of a Pre-Metastatic Niche

The term “pre-metastatic niche” refers to the microenvironment in a secondary organ that provides favorable conditions for colonization by tumor cells. It is required for CRLM development because, in the liver, the arriving tumor cells find immune cells, parenchymal and non-parenchymal liver cells, all contributing to create a hostile environment for the survival of cancer cells. Thus, the preparation of a pre-metastatic niche is an event occurring prior to the arrival of CRC cells, mandatory to escape immune surveillance and contemporarily transform the local stroma. The first contribution is made by the primary tumor itself, which prepares the distant niche by releasing secreted factors that, in turn, recruit KCs, HepSCc, MDSCs, and neutrophils [5]. In particular, HepSC activation plays a crucial role in the liver TME remodeling by secreting TGFβ, EGF, VEGF, insulin-like growth factor (IGF), and MMPs [50,89]. CRC cells produce VEGF-A, which stimulates the expression of the chemokine CXCL1 by TAMs in a primary tumor. Elevated levels of CXCL1 recruit CXCR2-positive MDSCs to pre-metastatic liver tissue and promote host immune response evasion, thus increasing tumor cell survival [23]. To achieve this goal, MDSCs attenuate the immunoreaction of NK cells by releasing nitric oxide, which interferes with NK cell functions [90]. Recently, it has been shown that STAT3 signaling in CRC cells results in the production of IL-6, which, in turn, is involved in the recruitment of MDSCs [33]. Studies have indicated that NOTCH1 signaling in a tumor induces TGFβ2 expression in the hepatic pre-metastatic niche, resulting in TGFβR1-dependent neutrophil recruitment to the liver. In turn, neutrophils inhibit cytotoxic T lymphocytes (CTLs, cells involved in the elimination of mutated and cancerous cells), thereby contributing to immunosuppression in pre-metastatic niches [91]. Further immunosuppression can be achieved through the recruitment of MDSCs by serum amyloid A1 and A2 (SSA1 and SSA2) proteins, released from parenchymal hepatocytes after IL-6-mediated STAT3 signaling activation [92]. CD4+ T lymphocytes include T helper 1 (Th1), T helper 2 (Th2), and regulatory T (Treg) cells. Th1 and Th2 cells are involved in the antitumor immune responses. In particular, Th1 lymphocytes stimulate macrophages to phagocytose, thus aiding cell-mediated killing. They exert their function by producing cytokines such as interferon γ (IFNγ) and TNFα. Instead, Th2 lymphocytes are involved in the activation of humoral immunity by secreting IL-4 [24]. Finally, Treg lymphocytes act to suppress immune responses, thus facilitating cancer immune evasion [21]. The immunosuppressive mechanism of action of Treg cells occurs partly by involving cytokines: Treg cells sequester high amounts of IL-2, thus lowering its availability for activating CTLs. On the other hand, Treg cells are able to inhibit the activation of CTLs by releasing IL-10, IL-35, and TGFβ [41,93]. In this context, TGFβ has been recognized not only as a strong inducer of the polarization of intratumor Tregs, but also as an important player in regulating Tregs’ motility across the endothelial layer, thus facilitating their recruitment at the tumor site [94]. The exposition to continuous cancer antigenic stimulation leads to the transformation of CD8+ T cells into a dysfunctional state, known as “exhaustion” [25]. These exhausted cells are impaired in promoting tumor-killing effects due to the loss of the effector function, that is, the ability to secrete effective cytokines, including IL-2, IFNγ, and TNFα [25]. Via CCL2/CCR2 signaling, CRC cells contribute to the formation of a favorable TME by controlling the recruitment of M2 macrophages [20]. In turn, M2 cells secrete cytokines such as CCL22, CCL17, IL-10, and TGFβ, which support an immunosuppressive microenvironment [42]. In addition, M2 macrophages contribute to cancer invasion by producing MMPs, which lead to matrix remodeling and thus facilitate metastasis [34]. Furthermore, it was demonstrated that IL-1β also contributes to cell invasion through the activation of protein kinases AP-1 and NF-kB by stimulating the overexpression of MMP-2 and MMP-9 [29]. The dendritic cells (DCs) in the liver inhibit T lymphocytes’ function by secreting high levels of IL-1 but low levels of IL-12, thus maintaining liver tolerance [45]. Tumor-associated neutrophils (TANs) are another immune cell type that contribute to the immunosuppression of the hepatic microenvironment. Indeed, TANs recruit M2 macrophages and Treg cells by producing CCL2 and CCL17. In turn, M2 and Treg cells favor the establishment of an immunosuppressive TME in the liver, thus promoting cancer progression and metastasis [95].
Several studies have highlighted a mechanism in which CRC-derived exosomes, which contain different kinds of bioactive molecules, promote the transformation of the liver TME [96]. For example, pancreatic cancer-derived exosomes contain a large amount of migration inhibitory factor (MIF), a cytokine which is taken up by KCs through fusions with exosomes. KCs respond by producing TGFβ, leading to the activation of HepSCs, and the subsequent deposition of fibronectin [56]. The blockade of MIF activity prevents liver metastases, thus confirming the importance of cytokines in mediating the adhesion of circulating tumor cells to distant sites in the metastatic cascade. Other well-known components of tumor cell-derived exosomes released by CRC cells are miRNAs, which also play a role in the pre-metastatic niche preparation. Exosomal miR-21-5p activates the polarization of KCs to the M2 phenotype, which in turn synthesizes IL-6, thereby creating an inflammatory pre-metastatic environment [97]. In a recent study, Zhao et al. found that the exosome cargo miR-181a-5p activates HepSCs by targeting SOCS3 and activating the IL-6/STAT3 signaling pathway. In turn, activated HepSCs remodel the liver microenvironment via the activation of the CCL20/CCR6 axis in CRC cells [22]. Tan et al. demonstrated that the interaction between CRC cells and HepSCs could promote the differentiation of HepSCs into CAFs via the TGF-β/CXCR4 axis [98]. Among the tumor-derived exosome cargo components there is also TGFβ, which is involved in the transformation of normal quiescent fibroblasts into CAFs, which modify the TME, as discussed above [57]. Finally, a recent study suggests that CRC-derived exosomes containing HSPC111, a ribosome component, reprogrammed the lipid metabolism in HepSCs, resulting in increased CXCL5 secretion that recruited tumor cells through the CXCL5-CXCR2 pathway [99].

2.3.2. Tumor Cell Dormancy

After the invasion of the liver pre-metastatic niche, tumor cells may enter a quiescent state called “tumor dormancy”. During this phase, CRC dormant cells enter the G0 phase of the cell cycle and express weak tumor antigens, thereby escaping immune surveillance, surviving and adapting in the changing microenvironment. Moreover, tumor dormant cells may go undetected for long periods, thus explaining the absence of clinical symptoms, until they awake as aggressive metastases. Several cytokines and signaling pathways have been proposed to be regulatory factors of tumor dormancy. Among them, the TGF family members TGFβ2 and bone morphogenetic protein 7 (BPM7) may activate p38 MAPK, which results in the inhibition of p21 and p27, leading to cell cycle arrest and cellular quiescence [58,100].

2.4. Angiogenic Phase

A metastatic vasculature is established through VEGF-dependent tumor angiogenesis. This process is essential for providing the oxygen and nutrients necessary for the growth of the primary tumor and metastases. Alternatively, existing blood vessels can be co-opted independently of VEGF, thus explaining why the majority of patients do not exhibit a response to an anti-VEGF agent in addition to chemotherapy [59]. Moreover, other molecules, such as fibroblast growth factor 2 (FGF2), secreted by neutrophils recruited to the liver, can promote the growth of metastasis and vascular remodeling in the liver [101]. HepSCs and CAFs are also involved in this phase because they produce proangiogenic factors such as VEGF, angiopoietin-1, and IL-8 [38,60]. In contrast, a reduction in CXCR2 diminishes tumor angiogenesis and enhances tumor necrosis [102]. CRC-derived IL-1α augments angiogenesis by modulating stromal cells within the TME and facilitates metastasis [103]. IL-17F may also be implicated, since its overexpression in HCT116 CRC cells inhibits angiogenesis and reduces tumor growth [104]. While endothelial cells (ECs) present in the innermost layer of blood vessels promote selective permeable exchange between the blood and tissue, tumor-associated ECs (TECs) do not form a regular single layer and do not have a normal barrier function [105]. TECs promote neovascularization and CRLM by secreting IL-33 [46]. TGFβ1, also secreted by CRC cells during this phase, exerts its prometastatic function by affecting the crosstalk between the tumor and TECs, thereby promoting angiogenesis. Thus, TGFβ1 silencing significantly reduces liver metastasis formation in vivo and suppresses angiogenesis in vitro [82]. IL-6 has a profound effect on enhancing angiogenesis through the activation of STAT3 signaling [35]. Finally, it has been demonstrated that IL-1β can also promote colon tumor growth, inducing angiogenesis [106].

2.5. Growth Phase

After blood vessels’ formation or co-option, metastatic tumor success depends on further tumor growth. A rigorous remodeling of local stroma is necessary and is accompanied by metabolic adaptations of disseminated CRC cells in order to allow them to grow out into macroscopic metastases. Signals from the liver microenvironment stimulate factors to escape dormancy and induce tumor growth. For example, the chemokine CCL7, secreted by MDSCs, binds to CCR2 on disseminated CRC cells, thereby activating the STAT3 signaling pathway, resulting in growth and colonization [44]. Similarly, GP130/STAT signaling induced by IL-11 derived from TGFβ-stimulated CAFs can suppress apoptosis and promote outgrowth to CRLM [107].

3. Cytokine Network and Therapy for CRLM

Cytokines have been known for their antitumoral efficacy since 1976, when a preclinical study demonstrated that treatment with human IFN had an antileukemic effect [108]. Since then, many cytokines have been investigated as potential therapeutic agents or targets. For example, a statistical analysis showed that CRC patients with low TNFα serum levels had a significantly higher survival rate compared to patients with high levels of TNFα [109]. Accordingly, a preclinical study showed that, in a CRC mouse model, the administration of Etanercept, a specific antagonist of TNFα, strongly decreased tumor progression [110]. Another report stated that blocking TNFα signaling reduces the number of liver metastases induced by human colorectal carcinoma CX-1 cells [111]. Moreover, a phase I trial has determined the side effects and best dose of NGR-hTNF, a fusion protein that delivers TNFα to tumors, in order to induce an antivascular effect (NCT00098943) [36]. In CRC, liver metastases are supported by CAFs, which are recruited to produce a prometastatic microenvironment through the activation of inflammatory IL-6 [36]. The genetic ablation of IL-6 reduces tumor development in colitis-associated colorectal cancer (CAC) [112]. Nowadays, a wide range of therapeutic approaches has been developed to target the IL-6/STAT3 pathway in the treatment of CRC [113]. IL-2 exerts its antitumor effect by stimulating T cell proliferation [21]; therefore, it is considered a potential drug candidate. This is reflected by a high number of clinical trials targeting IL-2. Among them, a phase I/II study is currently evaluating the safety and pharmacodynamics of MDNA11, a recombinant IL-2 engineered to preferentially activate immune effector cells (CD8+ T and NK cells) in patients with advanced solid tumors (NCT05086692). Many studies have reported that IL-1β plays a pivotal role in tumor growth and metastasis [114,115]. Indeed, the knockout of the IL-1 receptor (IL-1R) in the intestinal epithelium alleviated tumor formation and progression in mouse models of CRC [116]. Inhibitors at different levels of IL-1β synthesis and signaling pathways help in CRC therapy [117]. In addition, the human IL-1R antagonist Anakinra inhibits both IL-1 and its receptor, IL-1R, reducing metastatic CRC [118]. Recently, a phase III trial (NCT02138422) has revealed that Xilonix, a monoclonal antibody against IL-1alpha, not only slows tumor growth, but also improves symptoms of muscle loss, fatigue, and appetite loss in patients with CRC [47]. Emerging studies indicate that the IL-33/ST2 axis may be a new therapeutic target in CRC. Consistently, increased levels of IL-33 and increased IL-33+ microvessel densities occur in the stroma of adenomas and CRC. In support of this, the administration of the soluble form of the IL-33 receptor suppresses tumor growth by inhibiting IL-33-induced angiogenesis [48]. The CXCL12-CXCR4/CXCR7 axis is associated with recurrence and metastases in CRC [119]. Multiple antagonists of CXCR4 are currently tested in preclinical and clinical studies on various cancers. In particular, the CXCR4 inhibitor LY2510924 has been proven to be clinically safe in CRC and pancreatic cancers, with the primary response being 20% (NCT02737072) [120]. Nevertheless, targeting CXCR4 or CXCR7 alone is not sufficient for inhibiting tumor progression, suggesting that other pathways are activated and that both receptors need to be blocked [40]. More recently, Spiegelmers have been used as an alternative approach to inhibit the CXCL12-CXCR4/CXCR7 axis. These are synthetic oligonucleotides conjugated to polyethylene glycol to target CXCL12 and prevent binding to its receptors [121]. Currently, there is an ongoing phase II study on the Spiegelmer Olaptesed pegol combined with Pembrolizumab and nanoliposomal Irinotecan/5-FU/Leucovorin or Gemcitabine/Nab-paclitaxel in microsatellite-stable metastatic pancreatic and colorectal cancer patients (NCT04901741). TGFβ is a potent activator of the EMT, invasion, and metastasis by controlling different genes and proteins related to cell–cell adhesion and ECM remodeling [89]. Several classes of TGFβ-based therapies are currently undergoing clinical trials (https://clinicaltrials.gov/, accessed 4 September 2023): monoclonal neutralizing antibodies against TGFβ ligands, antisense oligonucleotides, small-molecule inhibitors, and gene therapy. For instance, an antisense oligonucleotide specific to the mRNA of TGFβ has been positively tested in a phase I trial on various solid cancers (NCT00844064). Additional studies are needed, for example, to determine whether an anti-TGFβRII monoclonal antibody (IMC-TR1) could be safe and tolerable in participants with solid tumors, including in CRC (NCT01646203). Moreover, the oncogenic and tumor-suppressive role of TGFβ, as well as the complexity of its function in the modulation of cellular and tissue homeostasis, often lead to unsatisfactory therapy outcomes [30]. IL-11 is highly expressed in human CRC and its receptor blockade can attenuate CRC xenograft growth. Based on this study and reports that TGFβ promotes metastasis by inducing IL-11 production by CAFs, IL-11 has emerged as another possible target to use in cancer therapy [43]. In addition, a randomized phase II trial has demonstrated that IL-11 is also effective for the treatment of chemotherapy-induced thrombocytopenia in patients with recurrent colorectal cancer (NCT03823079). Genetic variations in the genes encoding IL-8 and its receptor, CXCR2, are associated with CRC progression, therapeutic resistance, and tumor recurrence [37]. Indeed, antagonism of CXCR2 with the small molecule SCH-527123 impairs cell proliferation, motility, and invasiveness in CRC xenografts [122]. As of now, there are 29 distinct clinical trials targeting CXCR2; among CXCR2 antagonists, SX-682 is being tested in different malignancies such as melanoma, myelodysplastic syndromes, and pancreatic cancer. Further studies are required to test its efficacy in CRLM.
Cytokines have two main peculiarities: redundancy and pleiotropy. While the former means that different molecules exert the same effect, pleiotropy allows the same proteins to exert different effects. Therefore, cytokines are key players in carcinogenesis as they may exert pro- and antitumoral effects, which might also co-exist in different phases of the disease. Recent studies have focused more on targeting cytokine signaling to improve anticancer responses in CRLM. For example, IL-4 is involved in promoting the EMT in CRC, and it has been reported to protect CRC cells from apoptosis. Interestingly, the inhibition of IL-4 signaling blocks resistance to chemo-immunotherapeutic treatments [123]. On the other hand, complex cytokine interactions make it difficult to identify effective targets for therapeutic strategies. For example, IL-17 is an enhancer of CRC progression, and it has been shown that IL-17 and TNF synergize to promote carcinogenesis through the high production of growth factors by CRC cells [124]. IL-22 is another promoter factor of IL-17 activity. Indeed, although inhibiting IL-17 reduces intestinal inflammation, only IL-22 neutralization has been shown to significantly reduce the dysplasia and tumor burden in a mouse model of CRC [125]. Tumor-infiltrating leukocytes (TILs) secrete multiple cytokines that promote the proliferation of CRC cells both through STAT3 (induced by IL-6 and IL-22) and NF-kB (induced by TNFα and IL-17A) signaling pathways. Consistently, in vivo findings demonstrated that the proliferative stimulus could not be abolished through the inhibition of individual cytokines. Only the combinatorial blockade of IL-6, IL-22, TNFα, and IL-17A could effectively neutralize the mitogenic effect induced by TIL-secreted cytokines [53].
Cytokine families could also be broadly inhibited by targeting shared receptor subunits. For example, the blockading of GP130 can inhibit the signaling of several cytokines, including IL-6, IL-11, and leukemia inhibiting factor (LIF) [126]. Similarly, the blockading of IL-22RA1 can impair not only IL-22-induced signaling but also that of IL-20 and IL-24 [127]. Therapy with bispecific antibodies to target distinct cytokine pathways using a single therapeutic agent is an intriguing option for CRLM [128]. For example, the use of a novel anti-TGFβ/VEGFA bispecific antibody, Y332D, entirely counteracts the in vitro biological functions of TGFβ and VEGFA, including the EMT and immunosuppression. Consistently, the in vivo experiment data demonstrate that Y332D exerts a superior antitumor effect compared to anti-TGFβ and anti-VEGF monotherapies [129]. Similarly, several clinical trials have recently investigated the antitumor activity of a modified IL-2 in combination with both of the EGFR inhibitors Trastuzamab and Cetuximab (NCT02627274) and a monoclonal antibody targeting VEGF (NCT03063762).
To summarize the above findings, the multitude of protumorigenic cytokines involved in CRLM development implies that cytokine-based therapies may be advantageous; however, other considerations need to be made. As cytokines’ roles range from immune regulation to antimicrobial activity and responses to inflammation, altering cytokines’ signaling may significantly impair host immune homeostasis. In addition, conventional treatments that target cytokines are sometimes accompanied by toxic side effects such as headaches, fatigue, and injection site reactions. Thus, how can the side effects of cytokine-based therapy be reduced? A better approach would be to use a specific vehicle to precisely target selected cytokine signaling.

4. Conclusions

In this review, we summarized data indicating that cytokines promote several key hallmarks of cancer, including aberrant growth, angiogenesis, invasiveness, and metastasis. Preclinical and clinical research has led to the therapeutic use of cytokines in tumor therapy, and, more recently, in preventing CRC invasion as well as liver metastasis. Despite the overall success of current treatments, the prognosis of patients with liver metastases remains poor. Blocking protumorigenic elements and simultaneously promoting antitumor immunity may improve the efficacy of therapies; therefore, combining the manipulation of cytokine pathways with checkpoint blockading can represent a promising strategy. The current knowledge of cytokine biology and immunotherapy has led to an increase in the number of ongoing clinical trials involving more than one strategy; however, multitarget approaches have both positive and side effects, including systemic proinflammatory effects due to the use of cytokines. One approach could be targeting agents directly to the TME in order to neutralize the immunosuppressive function of cytokines. On the other hand, in this age of the expansion of precision and personalized medicine, it would be useful to develop novel prognostic biomarkers. Recent studies point to cytokines as potential biomarkers for diagnosis and monitoring the clinical outcomes of CRLM patients. The assays with which to detect cytokines still have a sensitivity limit due to the low concentration of cytokines, their thermal instability, and other factors. Therefore, future studies are needed to confirm the consistency of the results and their applicability.

Author Contributions

Conceptualization, C.B. and G.G.; writing—original draft preparation, C.B.; writing—review and editing, C.B., V.Q. and G.G.; supervision, G.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the following grants: TRANSCAN-3 JTC 2021-iParaCyts and Ricerca Corrente 2023 from the Italian Ministry of Health.

Acknowledgments

The authors thank Mary V.C. Pragnell, B.A. for language revision of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.L.; Wagle, N.S.; Cercek, A.; Smith, R.A.; Jemal, A. Colorectal cancer statistic, 2023. CA Cancer J. Clin. 2023, 73, 233–254. [Google Scholar] [CrossRef] [PubMed]
  2. Parkin, D.M.; Pisani, P.; Ferlay, J. Global cancer statistics. CA Cancer J. Clin. 1999, 49, 33–64. [Google Scholar] [CrossRef] [PubMed]
  3. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  4. Xi, Y.; Xu, P. Global colorectal cancer burden in 2020 and projections to 2040. Transl. Oncol. 2021, 14, 101174. [Google Scholar] [CrossRef] [PubMed]
  5. Milette, S.; Sicklick, J.K.; Lowy, A.M.; Brodt, P. Molecular Pathways: Targeting the Microenvironment of Liver Metastases. Clin. Cancer Res. 2017, 23, 6390–6399. [Google Scholar] [CrossRef]
  6. Valderrama-Treviño, A.I.; Barrera-Mera, B.; Ceballos-Villalva, J.C.; Montalvo-Javé, E.E. Hepatic Metastasis from Colorectal Cancer. Euroasian J. Hepatogastroenterol. 2017, 7, 166–175. [Google Scholar] [CrossRef]
  7. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. Cancer J. Clin. 2020, 70, 7–30. [Google Scholar] [CrossRef]
  8. Tai, D.; Choo, S.P.; Chew, V. Rationale of immunotherapy in hepatocellular carcinoma and its potential biomarkers. Cancers 2019, 11, 1926. [Google Scholar] [CrossRef]
  9. Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. Mass. Med. Soc. 2015, 372, 2521–2532. [Google Scholar] [CrossRef]
  10. Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015, 373, 1803–1813. [Google Scholar] [CrossRef]
  11. Fan, A.; Wang, B.; Wang, X.; Nie, Y.; Fan, D.; Zhao, X.; Lu, Y. Immunotherapy in colorectal cancer: Current achievements and future perspective. Int. J. Biol. Sci. 2021, 17, 3837–3849. [Google Scholar] [CrossRef] [PubMed]
  12. Andr, T.; Shiu, K.K.; Kim, T.W.; Jensen, B.W.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab in Microsatellite-instability-High -Advanced Colorectal Cancer. N. Engl. J. Med. 2020, 383, 2207–2218. [Google Scholar] [CrossRef] [PubMed]
  13. Ree, A.; Hamre, H.; Kersten, C.; Hofsli, E.; Guren, M.; Sorbye, H.; Johansen, C.; Negård, A.; Flatmark, K.; Meltzer, S. Repeat sequential oxaliplatin-based chemotherapy (FLOX) and nivolumab versus FLOX alone as first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Initial results from the randomized METIMMOX study. J. Clin. Oncol. 2021, 39, 3556. [Google Scholar] [CrossRef]
  14. Fakih, M.; Raghav, K.P.S.; Chang, D.Z.; Bendell, J.C.; Larson, T.; Cohn, A.L.; Huyck, T.K.; Cosgrove, D.; Fiorillo, J.A.; Garbo, L.E.; et al. Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC). J. Clin. Oncol. 2021, 39, 3560. [Google Scholar] [CrossRef]
  15. Binnewies, M.; Roberts, E.W.; Kersten, K.; Chan, V.; Fearon, D.F.; Merad, M.; Coussens, L.M.; Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Hedrick, C.C.; et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 2018, 24, 541–550. [Google Scholar] [CrossRef]
  16. Galindo-Pumariño, C.; Collado, M.; Herrera, M.; Peña, C. Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients’ Outcome. Cancers 2021, 13, 1130. [Google Scholar] [CrossRef]
  17. Bhat, A.A.; Nisar, S.; Singh, M.; Ashraf, B.; Masoodi, T.; Prasad, C.P.; Sharma, A.; Maacha, S.; Karedath, T.; Hashem, S.; et al. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun. 2022, 42, 689–715. [Google Scholar] [CrossRef]
  18. Cui, G. Immune battle at the premalignant stage of colorectal cancer: Focus on immune cell compositions, functions and cytokine products. Am. J. Cancer Res. 2020, 10, 1308–1320. [Google Scholar]
  19. Khatib, A.-M.; Auguste, P.; Fallavollita, L.; Wang, N.; Samani, A.; Kontogiannea, M.; Meterissian, S.; Brodt, P. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am. J. Pathol. 2005, 167, 749–759. [Google Scholar] [CrossRef]
  20. Komohara, Y.; Fujiwara, Y.; Ohnishi, K.; Takeya, M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv. Drug Deliv. Rev. 2016, 99, 180–185. [Google Scholar] [CrossRef]
  21. Nishikawa, H.; Koyama, S. Mechanisms of regulatory T cell infiltration in tumors: Implications for innovative immune precision therapies. J. Immunother. Cancer 2021, 9, e002591. [Google Scholar] [CrossRef] [PubMed]
  22. Tan, H.X.; Gong, W.Z.; Zhou, K.; Xiao, Z.G.; Hou, F.T.; Huang, T.; Zhang, L.; Dong, H.Y.; Zhang, W.L.; Liu, Y.; et al. CXCR4/TGFb1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol. Ther. 2020, 21, 258–268. [Google Scholar] [CrossRef] [PubMed]
  23. Wang, D.; Sun, H.; Wei, J.; Cen, B.; Dubois, R.N. CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res. 2017, 77, 3655–3665. [Google Scholar] [CrossRef] [PubMed]
  24. Lee, H.G.; Cho, M.Z.; Choi, J.M. Bystander CD4+ T cells: Crossroads between innate and adaptive immunity. Exp. Mol. Med. 2020, 52, 1255–1263. [Google Scholar] [CrossRef] [PubMed]
  25. Tu, W.; Gong, J.; Zhou, Z.; Tian, D.; Wang, Z. TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. Cell Death Dis. 2021, 12, 882. [Google Scholar] [CrossRef] [PubMed]
  26. Li, Y.; Wang, L.; Pappan, L.; Galliher-Beckley, A.; Shi, J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol. Cancer 2012, 11, 87. [Google Scholar] [CrossRef]
  27. Kaler, P.; Augenlicht, L.; Klampfer, L. Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: A crosstalk interrupted by vitamin D3. Oncogene 2009, 28, 3892–3902. [Google Scholar] [CrossRef]
  28. Brodt, P.; Fallavollita, L.; Bresalier, R.S.; Meterissian, S.; Norton, C.R.; Wolitzky, B.A. Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. Int. J. Cancer 1997, 71, 612–619. [Google Scholar]
  29. Xia, S.; Guo, Z.; Xu, X.; Yi, H.; Wang, Q.; Cao, X. Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance. Blood 2008, 112, 3175–3185. [Google Scholar] [CrossRef]
  30. Teixeira, A.F.; Ten Dijke, P.; Zhu, H.J. On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? Front. Cell Dev. Biol. 2020, 8, 605. [Google Scholar] [CrossRef]
  31. Sun, D.; Shen, W.; Zhang, F.; Fan, H.; Xu, C.; Li, L.; Tan, J.; Miao, Y.; Zhang, H.; Yang, Y.; et al. α-Hederin inhibits interleukin 6-induced epithelial-to-mesenchymal transition associated with disruption of JAK2/STAT3 signaling in colon cancer cells. Biomed. Pharmacother. 2018, 101, 107–114. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, J.; Cao, Z.; Zhang, X.M.; Nakamura, M.; Sun, M.; Hartman, J.; Harris, A.; Sun, Y.; Cao, Y. Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development. Cancer Res. 2015, 75, 306–315. [Google Scholar] [CrossRef] [PubMed]
  33. Lin, Q.; Ren, L.; Jian, M.; Xu, P.; Li, J.; Zheng, P.; Feng, Q.; Yang, L.; Ji, M.; Wei, Y.; et al. The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1–STAT3 signaling pathway. Cell Death Dis. 2019, 10, 693. [Google Scholar] [CrossRef] [PubMed]
  34. Kapral, M.; Wawszczyk, J.; Jurzak, M.; Hollek, A.; Węglarz, L. The effect of inositol hexaphosphate on the expression of selected metalloproteinases and their tissue inhibitors in IL-1β-stimulated colon cancer cells. Int. J. Colorectal Dis. 2012, 27, 1419–1428. [Google Scholar] [CrossRef] [PubMed]
  35. Baker, K.J.; Houston, A.; Brint, E. IL-1 Family Members in Cancer; Two Sides to Every Story. Front. Immunol. 2019, 10, 1197. [Google Scholar] [CrossRef] [PubMed]
  36. van Laarhoven, H.W.; Fiedler, W.; Desar, I.M.; van Asten, J.J.; Marréaud, S.; Lacombe, D.; Govaerts, A.S.; Bogaerts, J.; Lasch, P.; Timmer-Bonte, J.N.; et al. Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European Organization for Research and Treatment of Cancer Study 16041). Clin. Cancer Res. 2010, 16, 1315–1323. [Google Scholar] [CrossRef]
  37. Lurje, G.; Zhang, W.; Schultheis, A.M.; Yang, D.; Groshen, S.; Hendifar, A.E.; Husain, H.; Gordon, M.A.; Nagashima, F.; Chang, H.M.; et al. Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann. Oncol. 2008, 19, 1734–1741. [Google Scholar] [CrossRef]
  38. Lee, Y.S.; Choi, I.; Ning, Y.; Kim, N.Y.; Khatchadourian, V.; Yang, D.; Chung, H.K.; Choi, D.; LaBonte, M.J.; Ladner, R.D.; et al. Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. Br. J. Cancer 2012, 106, 1833–1841. [Google Scholar] [CrossRef]
  39. Ramadori, G.; Moriconi, F.; Malik, I.; Dudas, J. Physiology and pathophysiology of liver inflammation, damage and repair. J. Physiol. Pharmacol. 2008, 59 (Suppl. S1), 107–117. [Google Scholar]
  40. Khare, T.; Bissonnette, M.; Khare, S. CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies. Int. J. Mol. Sci. 2021, 22, 7371. [Google Scholar] [CrossRef]
  41. Collison, L.W.; Workman, C.J.; Kuo, T.T.; Boyd, K.; Wang, Y.; Vignali, K.M. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007, 450, 566–569. [Google Scholar] [CrossRef] [PubMed]
  42. Boutilier, A.J.; Elsawa, S.F. Macrophage Polarization States in the Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 6995. [Google Scholar] [CrossRef]
  43. Putoczki, T.L.; Thiem, S.; Loving, A.; Busuttil, R.A.; Wilson, N.J.; Ziegler, P.K.; Nguyen, P.M.; Preaudet, A.; Farid, R.; Edwards, K.M.; et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 2013, 24, 257–271. [Google Scholar] [CrossRef] [PubMed]
  44. Calon, A.; Espinet, E.; Palomo-Ponce, S.; Tauriello Daniele, V.F.; Iglesias, M.; Céspedes María, V.; Sevillano, M.; Nadal, C.; Jung, P.; Zhang, X.H.; et al. Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation. Cancer Cell 2012, 22, 571–584. [Google Scholar] [CrossRef] [PubMed]
  45. Zhou, S.L.; Zhou, Z.J.; Hu, Z.Q.; Huang, X.W.; Wang, Z.; Chen, E.B.; Fan, J.; Cao, Y.; Dai, Z.; Zhou, J. Tumor- Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology 2016, 150, 1646–1658.e17. [Google Scholar] [CrossRef]
  46. Lin, Y.; He, Z.; Ye, J.; Liu, Z.; She, X.; Gao, X.; Liang, R. Progress in understanding the IL-6/STAT3 pathway in colorectal cancer. Onco Targets Ther. 2020, 13, 13023–13032. [Google Scholar] [CrossRef]
  47. Hong, D.S.; Hui, D.; Bruera, E.; Janku, F.; Naing, A.; Falchook, G.S.; Piha-Paul, S.; Wheler, J.J.; Fu, S.; Tsimberidou, A.M.; et al. MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: An open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014, 15, 656–666. [Google Scholar] [CrossRef]
  48. Akimoto, M.; Maruyama, R.; Takamaru, H.; Ochiya, T.; Takenaga, K. Soluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment. Nat. Commun. 2016, 7, 13589. [Google Scholar] [CrossRef]
  49. Zhang, W.; Jiang, B.; Guo, Z.; Sardet, C.; Zou, B.; Lam, C.S.; Li, J.; He, M.; Lan, H.Y.; Pang, R.; et al. Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer. Carcinogenesis 2010, 31, 1220–1229. [Google Scholar] [CrossRef]
  50. Eynden, G.G.V.D.; Majeed, A.W.; Illemann, M.; Vermeulen, P.B.; Bird, N.C.; Høyer-Hansen, G.; Eefsen, R.L.; Reynolds, A.R.; Brodt, P. The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications. Cancer Res. 2013, 73, 2031–2043. [Google Scholar] [CrossRef]
  51. Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer 2009, 9, 361–371. [Google Scholar] [CrossRef]
  52. Wu, Y.; Deng, J.; Rychahou, P.G.; Qiu, S.; Evers, B.M.; Zhou, B.P. Stabilization of snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009, 15, 416–428. [Google Scholar] [CrossRef]
  53. De Simone, V.; Franzè, E.; Ronchetti, G.; Colantoni, A.; Fantini, M.C.; Di Fusco, D.; Sica, G.S.; Sileri, P.; MacDonald, T.T.; Pallone, F.; et al. Th17-type cytokines, IL-6 and TNF-synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene 2015, 34, 3493–3503. [Google Scholar] [CrossRef] [PubMed]
  54. Bates, R.C.; Mercurio, A.M. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol. Biol. Cell 2003, 14, 1790–1800. [Google Scholar] [CrossRef] [PubMed]
  55. Giannelli, G.; Koudelkova, P.; Dituri, F.; Mikulits, W. Role of Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma. J. Hepatol. 2016, 65, 798–808. [Google Scholar] [CrossRef] [PubMed]
  56. Shao, Y.; Chen, T.; Zheng, X.; Yang, S.; Xu, K.; Chen, X.; Xu, F.; Wang, L.; Shen, Y.; Wang, T.; et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 2018, 39, 1368–1379. [Google Scholar] [CrossRef]
  57. Zhang, C.; Wang, X.Y.; Zhang, P.; He, T.C.; Han, J.H.; Zhang, R.; Lin, J.; Fan, J.; Lu, L.; Zhu, W.W.; et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis. 2022, 13, 57. [Google Scholar] [CrossRef]
  58. Kobayashi, A.; Okuda, H.; Xing, F.; Pandey, P.R.; Watabe, M.; Hirota, S.; Pai, S.K.; Liu, W.; Fukuda, K.; Chambers, C.; et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 2011, 208, 2641–2655. [Google Scholar] [CrossRef]
  59. Gordon-Weeks, A.N.; Lim, S.Y.; Yuzhalin, A.E.; Jones, K.; Markelc, B.; Kim, K.J.; Buzzelli, J.N.; Fokas, E.; Cao, Y.; Smart, S.; et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 2017, 65, 1920–1935. [Google Scholar] [CrossRef]
  60. Watanabe, K.; Shiga, K.; Maeda, A.; Harata, S.; Yanagita, T.; Suzuki, T.; Ushigome, H.; Maeda, Y.; Hirokawa, T.; Ogawa, R.; et al. Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer. Int. J. Oncol. 2022, 60, 3. [Google Scholar] [CrossRef]
  61. Paget, S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1889, 8, 98–101. [Google Scholar] [CrossRef]
  62. Tiegs, G.A.; Lohse, W. Immune tolerance: What is unique about the liver. J. Autoimmun. 2010, 34, 1–6. [Google Scholar] [CrossRef] [PubMed]
  63. Lv, Y.; Patel, N.; Zhang, H.J. The progress of non-alcoholic fatty liver disease as the risk of liver metastasis in colorectal cancer. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 1169–1180. [Google Scholar] [CrossRef] [PubMed]
  64. Mohr, A.M.; Gould, J.J.; Kubik, J.L.; Talmon, G.A.; Casey, C.A.; Thomas, P.D.; Tuma, J.; McVicker, B.L. Enhanced colorectal cancer metastases in the alcohol-injured liver. Clin. Exp. Metastasis 2017, 34, 171–184. [Google Scholar] [CrossRef] [PubMed]
  65. Zeng, X.; Ward, S.E.; Zhou, J.; Cheng, A.S.L. Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives. Cancers 2021, 13, 2418. [Google Scholar] [CrossRef]
  66. Kim, J.; Takeuchi, H.; Lam, S.T.; Turner, R.R.; Wang, H.-J.; Kuo, C.; Foshag, L.; Bilchik, A.J.; Hoon, D.S. Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J. Clin. Oncol. 2005, 23, 2744–2753. [Google Scholar] [CrossRef]
  67. Ghadjar, P.; Coupland, S.E.; Na, I.-K.; Noutsias, M.; Letsch, A.; Stroux, A. Chemokine Receptor CCR6 Expression Level and Liver Metastases in Colorectal Cancer. J. Clin. Oncol. 2006, 24, 1910–1916. [Google Scholar] [CrossRef]
  68. Hu, Z.; Ding, J.; Ma, Z.; Sun, R.; Seoane, J.A.; Shaffer, J.S.; Suarez, C.J.; Berghoff, A.S.; Cremolini, C.; Falcone, A.; et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat. Genet. 2019, 51, 1113–1122. [Google Scholar] [CrossRef]
  69. Ryser, M.D.; Min, B.H.; Siegmund, K.D.; Shibata, D. Spatial mutation patterns as markers of early colorectal tumor cell mobility. Proc. Natl. Acad. Sci. USA 2018, 115, 5774–5779. [Google Scholar] [CrossRef]
  70. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84. [Google Scholar] [CrossRef]
  71. Toiyama, Y.; Yasuda, H.; Saigusa, S.; Tanaka, K.; Inoue, Y.; Goel, A. Increased expression of Slug and Vimentin as novel predictive biomarkers for lymph node metastasis and poor prognosis in colorectal cancer. Carcinogenesis 2013, 34, 2548–2557. [Google Scholar] [CrossRef] [PubMed]
  72. Valdés-Mora, F.; Gómez del Pulgar, T.; Bandrés, E.; Cejas, P.; Ramírez de Molina, A.; Pérez-Palacios, R.; Gallego-Ortega, D.; García-Cabezas, M.A.; Casado, E.; Larrauri, J.; et al. TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer. Ann. Surg. Oncol. 2009, 16, 78–87. [Google Scholar] [CrossRef] [PubMed]
  73. Wang, H.; Wang, H.S.; Zhou, B.H.; Li, C.L.; Zhang, F.; Wang, X.F.; Zhang, G.; Bu, X.Z.; Cai, S.H.; Du, J. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS ONE 2013, 8, e56664. [Google Scholar] [CrossRef] [PubMed]
  74. Zhao, P.; Zhang, Z. TNF-promotes colon cancer cell migration and invasion by upregulating TROP-2. Oncol. Lett. 2018, 15, 3820–3827. [Google Scholar] [CrossRef]
  75. Holmer, R.; Wätzig, G.H.; Tiwari, S.; Rose-John, S.; Kalthoff, H. Interleukin-6 trans-signaling increases the expression of carcinoembryonic antigen-related cell adhesion molecules 5 and 6 in colorectal cancer cells. BMC Cancer 2015, 15, 975. [Google Scholar] [CrossRef]
  76. Tyagi, A.; Sharma, A.K.; Damodaran, C. A review on notch signaling and colorectal cancer. Cells 2020, 9, 1549. [Google Scholar] [CrossRef]
  77. Lin, J.T.; Wang, J.Y.; Chen, M.K.; Chen, H.C.; Chang, T.H.; Su, B.W.; Chang, P.J. Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6. Exp. Cell Res. 2013, 319, 2216–2229. [Google Scholar] [CrossRef]
  78. Hwang, W.L.; Yang, M.H.; Tsai, M.L.; Lan, H.Y.; Su, S.H.; Chang, S.C.; Teng, H.W.; Yang, S.H.; Lan, Y.T.; Chiou, S.H.; et al. SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 2011, 141, 279–291. [Google Scholar] [CrossRef]
  79. Wang, X.; Yang, Z.; Tian, H.; Li, Y.; Li, M.; Zhao, W.; Zhang, C.; Wang, T.; Liu, J.; Zhang, A.; et al. Circulating MIC-1/GDF15 is a complementary screening biomarker with CEA and correlates with liver metastasis and poor survival in colorectal cancer. Oncotarget 2017, 8, 24892–24901. [Google Scholar] [CrossRef]
  80. Bellam, N.; Pasche, B. Tgf-beta signaling alterations and colon cancer. Cancer Treat. Res. 2010, 155, 85–103. [Google Scholar] [CrossRef]
  81. Zhao, M.; Mishra, L.; Deng, C.X. The role of TGF-β/SMAD4 signaling in cancer. Int. J. Biol. Sci. 2018, 14, 111–123. [Google Scholar] [CrossRef] [PubMed]
  82. Chiavarina, B.; Costanza, B.; Ronca, R.; Blomme, A.; Rezzola, S.; Chiodelli, P.; Giguelay, A.; Belthier, G.; Doumont, G.; Van Simaeys, G.; et al. Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis. Theranostics 2021, 11, 1626–1640. [Google Scholar] [CrossRef] [PubMed]
  83. Fransvea, E.; Angelotti, U.; Antonaci, S.; Giannelli, G. Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 2008, 47, 1557–1566. [Google Scholar] [CrossRef]
  84. Chiang, S.P.H.; Cabrera, R.M.; Segall, J.E. Tumor cell intravasation. Am. J. Physiol. 2016, 311, C1–C14. [Google Scholar] [CrossRef] [PubMed]
  85. Matsumura, H.; Kondo, T.; Ogawa, K.; Tamura, T.; Fukunaga, K.; Murata, S.; Ohkohchi, N. Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stage. Int. J. Oncol. 2014, 45, 2303–2310. [Google Scholar] [CrossRef] [PubMed]
  86. Leblanc, R.; Peyruchaud, O. Metastasis: New functional implications of platelets and megakaryocytes. Blood 2016, 128, 24–31. [Google Scholar] [CrossRef] [PubMed]
  87. Plantureux, L.; Mège, D.; Crescence, L.; Carminita, E.; Robert, S.; Cointe, S.; Brouilly, N.; Ezzedine, W.; Dignat-George, F.; Dubois, C.; et al. The interaction of platelets with colorectal cancer cells inhibits tumor growth but promotes metastasis. Cancer Res. 2020, 80, 291–303. [Google Scholar] [CrossRef]
  88. Auguste, P.; Fallavollita, L.; Wang, N.; Burnier, J.; Bikfalvi, A.; Brodt, P. The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. Am. J. Pathol. 2007, 170, 1781–1792. [Google Scholar] [CrossRef]
  89. Caja, L.; Dituri, F.; Mancarella, S.; Caballero-Diaz, D.; Moustakas, A.; Giannelli, G.; Fabregat, I. TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer. Int. J. Mol. Sci. 2018, 19, 1294. [Google Scholar] [CrossRef]
  90. Stiff, A.; Trikha, P.; Mundy-Bosse, B.; McMichael, E.; Mace, T.A.; Benner, B.; Kendra, K.; Campbell, A.; Gautam, S.; Abood, D.; et al. Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function. Clin. Cancer Res. 2018, 24, 1891–1904. [Google Scholar] [CrossRef]
  91. Jackstadt, R.; van Hooff, S.R.; Leach, J.D.; Cortes-Lavaud, X.; Lohuis, J.O.; Ridgway, R.A.; Wouters, V.M.; Roper, J.; Kendall, T.J.; Roxburgh, C.S.; et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor prognosis subtypes and metastasis. Cancer Cell 2019, 36, 319–336.e7. [Google Scholar] [CrossRef] [PubMed]
  92. Lee, J.W.; Stone, M.L.; Porrett, P.M.; Thomas, S.K.; Komar, C.A.; Li, J.H.; Delman, D.; Graham, K.; Gladney, W.L.; Hua, X.; et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 2019, 567, 249–252. [Google Scholar] [CrossRef] [PubMed]
  93. Dituri, F.; Mancarella, S.; Serino, G.; Chaoul, N.; Lupo, L.G.; Villa, E.; Fabregat, I.; Giannelli, G. Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment. Int. J. Mol. Sci. 2021, 22, 11765. [Google Scholar] [CrossRef]
  94. van der Leun, A.M.; Thommen, D.S.; Schumacher, T.N. CD8+ T cell states in human cancer: Insights from single-cell analysis. Nat. Rev. Cancer 2020, 20, 218–232. [Google Scholar] [CrossRef] [PubMed]
  95. Lafitte, M.; Lecointre, C.; Roche, S. Roles of exosomes in metastatic colorectal cancer. Am. J. Physiol. Cell Physiol. 2019, 317, C869–C880. [Google Scholar] [CrossRef]
  96. Costa-Silva, B.; Aiello, N.M.; Ocean, A.J.; Singh, S.; Zhang, H.; Thakur, B.K.; Becker, A.; Hoshino, A.; Mark, M.T.; Molina, H.; et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 2015, 17, 816–826. [Google Scholar] [CrossRef]
  97. Zhao, S.; Mi, Y.; Zheng, B.; Wei, P.; Gu, Y.; Zhang, Z.; Xu, Y.; Cai, S.; Li, X.; Li, D. Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. J. Extracell. Vesicles 2022, 11, e12186. [Google Scholar] [CrossRef]
  98. Rai, A.; Greening, D.W.; Chen, M.; Xu, R.; Ji, H.; Simpson, R.J. Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome. Proteomics 2019, 19, e1800148. [Google Scholar] [CrossRef]
  99. Bragado, P.; Estrada, Y.; Parikh, F.; Krause, S.; Capobianco, C.; Farina, H.G.; Schewe, D.M.; Aguirre-Ghiso, J.A. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nat. Cell Biol. 2013, 15, 1351–1361. [Google Scholar] [CrossRef]
  100. Frentzas, S.; Simoneau, E.; Bridgeman, V.L.; Vermeulen, P.B.; Foo, S.; Kostaras, E.; Nathan, M.; Wotherspoon, A.; Gao, Z.H.; Shi, Y.; et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 2016, 22, 1294–1302. [Google Scholar] [CrossRef]
  101. Mueller, L.; Goumas, F.A.; Affeldt, M.; Sandtner, S.; Gehling, U.M.; Brilloff, S.; Walter, J.; Karnatz, N.; Lamszus, K.; Rogiers, X.; et al. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am. J. Pathol. 2007, 171, 1608–1618. [Google Scholar] [CrossRef] [PubMed]
  102. Matsuo, Y.; Sawai, H.; Ma, J.; Xu, D.; Ochi, N.; Yasuda, A.; Takahashi, H.; Funahashi, H.; Takeyama, H. IL- 1alpha secreted by colon cancer cells enhances angiogenesis: The relationship between IL-1alpha release and tumor cells’ potential for liver metastasis. J. Surg. Oncol. 2009, 99, 361–367. [Google Scholar] [CrossRef] [PubMed]
  103. Tong, Z.; Yang, X.O.; Yan, H.; Liu, W.; Niu, X.; Shi, Y.; Fang, W.; Xiong, B.; Wan, Y.; Dong, C. A protective role by interleukin-17F in colon tumorigenesis. PLoS ONE 2012, 7, e34959. [Google Scholar] [CrossRef] [PubMed]
  104. Chen, W.Z.; Jiang, J.X.; Yu, X.Y.; Xia, W.J.; Yu, P.X.; Wang, K.; Zhao, Z.Y.; Chen, Z.G. Endothelial cells in colorectal cancer. World J. Gastrointest. Oncol. 2019, 11, 946–956. [Google Scholar] [CrossRef]
  105. Zhang, Y.; Davis, C.; Shah, S.; Hughes, D.; Ryan, J.C.; Altomare, D.; Peña, M.M. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol. Carcinog. 2017, 56, 272–287. [Google Scholar] [CrossRef]
  106. Ren, X.; Xiao, J.; Zhang, W.; Wang, F.; Yan, Y.; Wu, X.; Zeng, Z.; He, Y.; Yang, W.; Liao, W.; et al. Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer. Cell Death Dis. 2021, 12, 484. [Google Scholar] [CrossRef]
  107. Rabin, H.; Adamson, R.H.; Neubauer, R.H.; Cicmanec, J.L.; Wallen, W.C. Pilot studies with human interferon in Herpesvirus saimiri-induced lymphoma in owl monkeys. Cancer Res. 1976, 36, 715–719. [Google Scholar]
  108. Donnelly, R.P.; Young, H.A.; Rosenberg, A.S. An overview of cytokines and cytokine antagonists as therapeutic agents. Ann. N. Y. Acad. Sci. 2009, 1182, 1–13. [Google Scholar] [CrossRef]
  109. Popivanova, B.K.; Kitamura, K.; Wu, Y.; Kondo, T.; Kagaya, T.; Kaneko, S.; Oshima, M.; Fujii, C.; Mukaida, N. Blocking TNF- in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Investig. 2008, 118, 560–570. [Google Scholar] [CrossRef]
  110. Jiao, S.F.; Sun, K.; Chen, X.J.; Zhao, X.; Cai, N.; Liu, Y.J.; Xu, L.M.; Kong, X.M.; Wei, L.X. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury. J. Biomed. Sci. 2014, 21, 1. [Google Scholar] [CrossRef]
  111. Tommelein, J.; Verset, L.; Boterberg, T.; Demetter, P.; Bracke, M.; DeWever, O. Cancer-associated fibroblasts connect metastasis promoting communication in colorectal cancer. Front. Oncol. 2015, 5, 63. [Google Scholar] [CrossRef] [PubMed]
  112. Han, J.; Xi, Q.; Meng, Q.; Liu, J.; Zhang, Y.; Han, Y.; Zhuang, Q.; Jiang, Y.; Ding, Q.; Wu, G. Interleukin-6 promotes tumor progression in colitis-associated colorectal cancer through HIF-1regulation. Oncol. Lett. 2016, 12, 4665–4670. [Google Scholar] [CrossRef] [PubMed]
  113. Waldner, M.J.; Foersch, S.; Neurath, M.F. Interleukin-6–a key regulator of colorectal cancer development. Int. J. Biol. Sci. 2012, 8, 1248–1253. [Google Scholar] [CrossRef] [PubMed]
  114. Ray, A.L.; Berggren, K.L.; Restrepo Cruz, S.; Gan, G.N.; Beswick, E.J. Inhibition of MK2 suppresses IL-1β, IL-6, and TNF-α-dependent colorectal cancer growth. Int. J. Cancer 2018, 142, 1702–1711. [Google Scholar] [CrossRef] [PubMed]
  115. Qian, H.; Zhang, D.; Bao, C. Two variants of Interleukin-1B gene are associated with the decreased risk, clinical features, and better overall survival of colorectal cancer: A two-center case-control study. Aging 2018, 10, 4084–4092. [Google Scholar] [CrossRef]
  116. Dmitrieva-Posocco, O.; Dzutsev, A.; Posocco, D.F.; Hou, V.; Yuan, W.; Thovarai, V.; Mufazalov, I.A.; Gunzer, M.; Shilovskiy, I.P.; Khaitov, M.R.; et al. Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer. Immunity 2019, 50, 166–180l. [Google Scholar] [CrossRef]
  117. Litmanovich, A.; Khazim, K.; Cohen, I. The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Thera-peutic Target in Clinical Practice. Oncol. Ther. 2018, 6, 109–127. [Google Scholar] [CrossRef]
  118. Isambert, N.; Hervieu, A.; Rébé, C.; Hennequin, A.; Borg, C.; Zanetta, S.; Chevriaux, A.; Richard, C.; Derangère, V.; Limagne, E.; et al. Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): A single-arm phase 2 study. Oncoimmunology 2018, 7, e1474319. [Google Scholar] [CrossRef]
  119. Kim, J.; Mori, T.; Chen, S.L.; Amersi, F.F.; Martinez, S.R.; Kuo, C.; Turner, R.R.; Ye, X.; Bilchik, A.J.; Morton, D.L.; et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann. Surg. 2006, 244, 113–120. [Google Scholar] [CrossRef]
  120. Galsky, M.D.; Vogelzang, N.J.; Conkling, P.; Raddad, E.; Polzer, J.; Roberson, S.; Stille, J.R.; Saleh, M.; Thornton, D. A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer. Clin. Cancer Res. 2014, 20, 3581–3588. [Google Scholar] [CrossRef]
  121. Vater, A.; Klussmann, S. Turning mirror-image oligonucleotides into drugs: The evolution of Spiegelmer(®) therapeutics. Drug Discov. Today 2015, 20, 147–155. [Google Scholar] [CrossRef] [PubMed]
  122. Ning, Y.; Labonte, M.J.; Zhang, W.; Bohanes, P.O.; Gerger, A.; Yang, D.; Benhaim, L.; Paez, D.; Rosenberg, D.O.; Nagulapalli Venkata, K.C.; et al. The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models. Mol. Cancer Ther. 2012, 11, 1353–1364. [Google Scholar] [CrossRef] [PubMed]
  123. Todaro, M.; Perez Alea, M.; Scopelliti, A.; Medema, J.P.; Stassi, G. IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle 2008, 7, 309–313. [Google Scholar] [CrossRef] [PubMed]
  124. Cui, G.; Yuan, A.; Goll, R.; Florholmen, J. IL-17A in the tumor microenvironment of the human colorectal adenoma-carcinoma sequence. Scand. J. Gastroenterol. 2012, 47, 1304–1312. [Google Scholar] [CrossRef]
  125. Kirchberger, S.; Royston, D.J.; Boulard, O.; Thornton, E.; Franchini, F.; Szabady, R.L.; Harrison, O.; Powrie, F. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 2013, 210, 917–931. [Google Scholar] [CrossRef] [PubMed]
  126. Heinrich, P.C.; Behrmann, I.; Haan, S.; Hermanns, H.M.; Müller-Newen, G.; Schaper, F. Principles of interleukin (IL)-6-typecytokine signalling and its regulation. Biochem. J. 2003, 374, 1–20. [Google Scholar] [CrossRef]
  127. Sabat, R.; Ouyang, W.; Wolk, K. Therapeutic opportunities of the IL 22–IL 22R1 system. Nat. Rev. Drug Discov. 2014, 13, 21–38. [Google Scholar] [CrossRef]
  128. Byrne, H.; Conroy, P.J.; Whisstock, J.C.; O’Kennedy, R.J. A tale of two specificities: Bispecific antibodies for therapeutic and diagnostic applications. Trends Biotechnol. 2013, 31, 621–632. [Google Scholar] [CrossRef]
  129. Niu, M.; Yi, M.; Wu, Y.; Lyu, L.; He, Q.; Yang, R.; Zeng, L.; Shi, J.; Zhang, J.; Zhou, P.; et al. Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy. J. Hematol. Oncol. 2023, 16, 94. [Google Scholar] [CrossRef]
Cancers 15 05359 g001
Figure 1. Liver metastasis cascade in CRC. Schematic representation of CRLM development through four overlapping phases: (1) microvascular, (2) extravascular, (3) angiogenic, and (4) growth. Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic lymphocyte; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; HepSC, hepatic stellate cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; Th1, T helper 1 lymphocyte; and Treg, regulatory T lymphocyte. Created with BioRender.com.
Figure 1. Liver metastasis cascade in CRC. Schematic representation of CRLM development through four overlapping phases: (1) microvascular, (2) extravascular, (3) angiogenic, and (4) growth. Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic lymphocyte; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; HepSC, hepatic stellate cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; Th1, T helper 1 lymphocyte; and Treg, regulatory T lymphocyte. Created with BioRender.com.
Cancers 15 05359 g001
Cancers 15 05359 g002
Figure 2. Cytokines in the pathogenesis of CRLM. Schematic representation of the cytokines involved during the different phases of CRLM development. For each phase, the contributions of the key cellular components of the CRC TME and the major cytokines involved are indicated. Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic lymphocyte; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; HepSC, hepatic stellate cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; TEC, tumor endothelial cell; Th1, T helper 1 lymphocyte; and Treg, regulatory T lymphocyte. Created with BioRender.com.
Figure 2. Cytokines in the pathogenesis of CRLM. Schematic representation of the cytokines involved during the different phases of CRLM development. For each phase, the contributions of the key cellular components of the CRC TME and the major cytokines involved are indicated. Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic lymphocyte; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; HepSC, hepatic stellate cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; TEC, tumor endothelial cell; Th1, T helper 1 lymphocyte; and Treg, regulatory T lymphocyte. Created with BioRender.com.
Cancers 15 05359 g002
Table 1. Main cytokines involved in CRLM development.
Table 1. Main cytokines involved in CRLM development.
CytokineCellular Source(s)Effects on CRLMReference
CCL2Cancer cellsPromotes immune cell recruitment, inflammation, and angiogenesis[19,20]
CCL20Cancer cellsPromotes the recruitment of Tregs and Th2 cells, metastasis, and TME remodeling[21,22]
CXCL1TAMsPromotes immune response[23]
IFNγTh1 cells and TECsPromotes angiogenesis, inflammation, and immune responses[24,25]
IL-1 βTAMs, CAFs, neutrophils, and KCsPromotes cancer cell proliferation, the EMT, and TME remodeling[26,27,28,29]
IL-4Th2 cellsPromotes inflammation and immune responses[19,24,30]
IL-6M1 macrophages, neutrophils, TECs, CAFs, and cancer cellsPromotes inflammation, migration, angiogenesis, cancer cell proliferation, and immune responses[31,32,33,34,35,36]
IL-8TAMs, T cells, ECs, HepSCs, CAFs, and cancer cellsPromotes cancer cell proliferation, angiogenesis, metastasis, an immunosuppressive TME, and chemoresistance[37,38,39,40]
IL-10M2 macrophages, Th2 cells, and TregsPromotes inflammation, cancer cell proliferation, cancer progression, and immunosuppression[41,42]
IL-11CAFsPromotes inflammation and cancer cell proliferation[43,44]
IL-12M1 macrophages and neutrophilsPromotes inflammation[45]
IL-13Th2 cells and CAFsPromotes inflammation, immunosuppression, and immune responses[19]
IL-17ANeutrophils, cancer cells, and CAFsPromotes cancer cell proliferation and chemoresistance[37,43]
IL-22CD4+ T cellsPromotes cancer cell proliferation and chemoresistance[37]
IL-33TECs and cancer cellsAngiogenesis[46,47,48]
MMPsCAFs, TAMs, cancer cells, and HepSCsTME remodeling[29,34,49,50]
TNFαM1 macrophages, TECs, KCs, and Th1 cellsPromotes inflammation, the EMT, migration, extravasion, angiogenesis, immune responses, immunosuppression, and M2 macrophage polarization[24,25,28,32,51,52,53,54]
TGFβCAFs, M2 macrophages, Tregs, neutrophils, MDSCs, HepSCs, and cancer cells Promotes the EMT, inflammation, immunosuppression, macrophage M2 polarization, fibroblast activation, and angiogenesis[39,41,44,49,55,56,57,58]
VEGFTECs, cancer cells, HepSCs, and CAFsPromotes inflammation, immune responses, and angiogenesis[38,59,60]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ballarò, C.; Quaranta, V.; Giannelli, G. Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers 2023, 15, 5359. https://doi.org/10.3390/cancers15225359

AMA Style

Ballarò C, Quaranta V, Giannelli G. Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers. 2023; 15(22):5359. https://doi.org/10.3390/cancers15225359

Chicago/Turabian Style

Ballarò, Costanza, Valeria Quaranta, and Gianluigi Giannelli. 2023. "Colorectal Liver Metastasis: Can Cytokines Make the Difference?" Cancers 15, no. 22: 5359. https://doi.org/10.3390/cancers15225359

APA Style

Ballarò, C., Quaranta, V., & Giannelli, G. (2023). Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers, 15(22), 5359. https://doi.org/10.3390/cancers15225359

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop