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Tumor Secretome in Translational Oncology
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Tumor Secretome in Translational Oncology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 19388

Special Issue Editor

Dr. Mario Cioce

E-Mail Website
Guest Editor
Laboratory of Molecular Medicine and Biotechnology, Department of Medicine, University Campus Bio-Medico of Rome, 00128 Rome, Italy
Interests: translational oncology; resistance to therapy; secretome signaling; microRNAs; cell transformation; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumor adaptation to stress impinges on resistance to therapy. Therapy-instigated secretome rearrangement instructs the tumor microenvironment adaptive response, possibly through altered cell subpopulation dynamics. The reshaping of secretome in therapy-resistant tumors is documented in many experimental settings (mesothelioma, NSCLC, melanoma, TNBC) and in some cases was shown to involve therapy-induced senescence, according to an SASP model. Cell autonomous and non-cell autonomous mechanisms cooperate to establish such a detrimental network, with a two-way communication among tumor and stroma. Secreted molecules may be pro-inflammatory cytokines, metabolites, or nucleic acids, in an ever growing list. Here, we consider how the tumor secretome influences response to therapy (including immunotherapy) and, mechanistically, how the effector molecules signal to the TME. We will consider TKIs, lipid signalling inhibitors, metabolic modulators, and senolytic drugs potentially interfering with the described processes and, therefore, of potential translational relevance in oncology.

Dr. Mario Cioce
Guest Editor

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Keywords

  • tumor microenvironment
  • cell subpopulations
  • lipid signaling
  • tumor secretome
  • metabolic targeting
  • therapy-induced stress
  • SASP

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Published Papers (5 papers)

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Research

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31 pages, 5262 KiB  
Article
Targeted Therapy Modulates the Secretome of Cancer-Associated Fibroblasts to Induce Resistance in HER2-Positive Breast Cancer
by Melani Luque, Marta Sanz-Álvarez, Andrea Santamaría, Sandra Zazo, Ion Cristóbal, Lorena de la Fuente, Pablo Mínguez, Pilar Eroles, Ana Rovira, Joan Albanell, Juan Madoz-Gúrpide and Federico Rojo
Int. J. Mol. Sci. 2021, 22(24), 13297; https://doi.org/10.3390/ijms222413297 - 10 Dec 2021
Cited by 10 | Viewed by 3972
Abstract
The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. [...] Read more.
The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. It is well known that the tumour microenvironment (TME) has a significant impact on cancer behaviour. Cancer-associated fibroblasts (CAFs) are essential components of the tumour stroma that have been linked to acquired therapeutic resistance and poor prognosis in breast cancer. For this reason, it would be of interest to identify novel biomarkers in the tumour stroma that could emerge as therapeutic targets for the modulation of resistant phenotypes. Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of the CAF-conditioned medium that may be relevant in the promotion of BCCL resistance, we implemented a multiomics strategy to identify cytokines, transcription factors, kinases and miRNAs in the secretome that have specific targets in cancer cells. The combination of cytokine arrays, label-free LC-MS/MS quantification and miRNA analysis to explore the secretome of CAFs under treatment conditions revealed several up- and downregulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer. Full article
(This article belongs to the Special Issue Tumor Secretome in Translational Oncology)
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15 pages, 3803 KiB  
Article
Melanoma Associated Chitinase 3-Like 1 Promoted Endothelial Cell Activation and Immune Cell Recruitment
by Gustavo Ramos-Espinosa, Yuanyuan Wang, Johanna M. Brandner, Stefan W. Schneider and Christian Gorzelanny
Int. J. Mol. Sci. 2021, 22(8), 3912; https://doi.org/10.3390/ijms22083912 - 10 Apr 2021
Cited by 10 | Viewed by 2849
Abstract
Chitinase 3-like 1 (CHI3L1) is an enzymatically inactive mammalian chitinase that is associated with tumor inflammation. Previous research indicated that CHI3L1 is able to interact with different extracellular matrix components, such as heparan sulfate. In the present work, we investigated whether the interaction [...] Read more.
Chitinase 3-like 1 (CHI3L1) is an enzymatically inactive mammalian chitinase that is associated with tumor inflammation. Previous research indicated that CHI3L1 is able to interact with different extracellular matrix components, such as heparan sulfate. In the present work, we investigated whether the interaction of CHI3L1 with the extracellular matrix of melanoma cells can trigger an inflammatory activation of endothelial cells. The analysis of the melanoma cell secretome indicated that CHI3L1 increases the abundance of various cytokines, such as CC-chemokine ligand 2 (CCL2), and growth factors, such as vascular endothelial growth factor A (VEGF-A). Using a solid-phase binding assay, we found that heparan sulfate-bound VEGF-A and CCL2 were displaced by recombinant CHI3L1 in a dose-dependent manner. Microfluidic experiments indicated that the CHI3L1 altered melanoma cell secretome promoted immune cell recruitment to the vascular endothelium. In line with the elevated VEGF-A levels, CHI3L1 was also able to promote angiogenesis through the release of extracellular matrix-bound pro-angiogenic factors. In conclusion, we showed that CHI3L1 is able to affect the tumor cell secretome, which in turn can regulate immune cell recruitment and blood vessel formation. Accordingly, our data suggest that the molecular targeting of CHI3L1 in the course of cancer immunotherapies can tune patients’ response and antitumoral inflammation. Full article
(This article belongs to the Special Issue Tumor Secretome in Translational Oncology)
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Review

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22 pages, 1478 KiB  
Review
Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential
by Peter R. McHenry and Jenifer R. Prosperi
Int. J. Mol. Sci. 2023, 24(3), 2100; https://doi.org/10.3390/ijms24032100 - 20 Jan 2023
Cited by 11 | Viewed by 4463
Abstract
The cancer secretome comprises factors secreted by tumors, including cytokines, growth factors, proteins from the extracellular matrix (ECM), proteases and protease inhibitors, membrane and extracellular vesicle proteins, peptide hormones, and metabolic proteins. Secreted proteins provide an avenue for communication with other tumor cells [...] Read more.
The cancer secretome comprises factors secreted by tumors, including cytokines, growth factors, proteins from the extracellular matrix (ECM), proteases and protease inhibitors, membrane and extracellular vesicle proteins, peptide hormones, and metabolic proteins. Secreted proteins provide an avenue for communication with other tumor cells and stromal cells, and these in turn promote tumor growth and progression. Breast cancer is the most commonly diagnosed cancer in women in the US and worldwide. Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and its lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2, making it unable to be treated with therapies targeting these protein markers, and leaving patients to rely on standard chemotherapy. In order to develop more effective therapies against TNBC, researchers are searching for targetable molecules specific to TNBC. Proteins in the TNBC secretome are involved in wide-ranging cancer-promoting processes, including tumor growth, angiogenesis, inflammation, the EMT, drug resistance, invasion, and development of the premetastatic niche. In this review, we catalog the currently known proteins in the secretome of TNBC tumors and correlate these secreted molecules with potential therapeutic opportunities to facilitate translational research. Full article
(This article belongs to the Special Issue Tumor Secretome in Translational Oncology)
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14 pages, 1685 KiB  
Review
Lymphatics in Tumor Progression and Immunomodulation
by Claire Y. Li, Stav Brown, Babak J. Mehrara and Raghu P. Kataru
Int. J. Mol. Sci. 2022, 23(4), 2127; https://doi.org/10.3390/ijms23042127 - 15 Feb 2022
Cited by 8 | Viewed by 3013
Abstract
The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. [...] Read more.
The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. While lymphatic proliferation and remodeling promote tumor dissemination, functional lymphatics are necessary for generating an effective immune response. Recent reports have noted lymphatic-dependent effects on the efficacy of immunotherapy. These findings suggest that the impact of lymphatic vessels on tumor progression is organ- and context-specific and that a greater understanding of the interaction of tumor cells, lymphatics, and the tumor microenvironment can unveil novel therapies. Full article
(This article belongs to the Special Issue Tumor Secretome in Translational Oncology)
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16 pages, 2171 KiB  
Review
NGAL as a Potential Target in Tumor Microenvironment
by Elvira Crescenzi, Antonio Leonardi and Francesco Pacifico
Int. J. Mol. Sci. 2021, 22(22), 12333; https://doi.org/10.3390/ijms222212333 - 15 Nov 2021
Cited by 22 | Viewed by 4060
Abstract
The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling [...] Read more.
The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy. Full article
(This article belongs to the Special Issue Tumor Secretome in Translational Oncology)
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