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Tumor Microenvironment and Treatment Resistance

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 20643

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Special Issue Editor

Dr. Zahid Pranjol

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Guest Editor

School of Life Sciences, University of Sussex, Falmer Brighton BN1 9RH, UK
Interests: tumor microenvironment; immunity; angiogenesis; ovarian cancer; breast cancer; endometrial cancer; glioblastoma; treatments; resistance

Special Issue Information

Dear Colleagues,

Cancer cells can resist therapeutic interventions through innate or acquired mechanisms, posing a significant challenge to chemotherapy, radiation and targeted therapy. Both primary and metastatic sites can contribute to cancer cell resistance via cell intrinsic and extrinsic factors, with the latter often overlooked. Evidence suggests that the tumor microenvironment (TME) plays a critical role in promoting therapeutic resistance by reducing drug penetration, conferring proliferative and antiapoptotic advantages, and facilitating resistance without genetic mutations or epigenetic changes. These changes can alter disease progression and clinical outcomes.

Recent studies have initiated the exploration of the complex relationship between cancer resistance and TME in pathological conditions. The findings suggest that the tumor microenvironment plays a crucial role in regulating immune escape, progression and distant metastasis of cancer. Although chemotherapy and radiotherapy have made considerable progress, the emergence of therapeutic resistance limits their effectiveness.

This Special Issue focuses on how the interplay between tumor cells and the surrounding cells in the microenvironment poses treatment resistance. The aim is to collect new ideas, concepts and findings in the field of cancer (e.g., epigenetics, immunosuppression, drug delivery and penetration, etc.) and treatment strategies (e.g., nanomedicine, immunotherapy, etc.).

Dr. Zahid Pranjol
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

tumor microenvironment
epigenetics
immunity
stiffness
resistant to treatment
metastasis
drug delivery
nanomedicine
immunotherapy
signaling
angiogenesis

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Published Papers (9 papers)

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Review

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35 pages, 3486 KiB

Open AccessReview

Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance

by Abdulaziz M. Eshaq, Thomas W. Flanagan, Sofie-Yasmin Hassan, Sara A. Al Asheikh, Waleed A. Al-Amoudi, Simeon Santourlidis, Sarah-Lilly Hassan, Maryam O. Alamodi, Marcelo L. Bendhack, Mohammed O. Alamodi, Youssef Haikel, Mossad Megahed and Mohamed Hassan

Cancers 2024, 16(15), 2754; https://doi.org/10.3390/cancers16152754 - 2 Aug 2024

Cited by 1 | Viewed by 1235

Abstract

Protein tyrosine kinases (PTKs) function as key molecules in the signaling pathways in addition to their impact as a therapeutic target for the treatment of many human diseases, including cancer. PTKs are characterized by their ability to phosphorylate serine, threonine, or tyrosine residues and can thereby rapidly and reversibly alter the function of their protein substrates in the form of significant changes in protein confirmation and affinity for their interaction with protein partners to drive cellular functions under normal and pathological conditions. PTKs are classified into two groups: one of which represents tyrosine kinases, while the other one includes the members of the serine/threonine kinases. The group of tyrosine kinases is subdivided into subgroups: one of them includes the member of receptor tyrosine kinases (RTKs), while the other subgroup includes the member of non-receptor tyrosine kinases (NRTKs). Both these kinase groups function as an “on” or "off" switch in many cellular functions. NRTKs are enzymes which are overexpressed and activated in many cancer types and regulate variable cellular functions in response to extracellular signaling-dependent mechanisms. NRTK-mediated different cellular functions are regulated by kinase-dependent and kinase-independent mechanisms either in the cytoplasm or in the nucleus. Thus, targeting NRTKs is of great interest to improve the treatment strategy of different tumor types. This review deals with the structure and mechanistic role of NRTKs in tumor progression and resistance and their importance as therapeutic targets in tumor therapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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26 pages, 3481 KiB

Open AccessReview

Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics

by Shraddha Shravani Peri, Krithicaa Narayanaa Y, Therese Deebiga Hubert, Roshini Rajaraman, Frank Arfuso, Sandhya Sundaram, B. Archana, Sudha Warrier, Arun Dharmarajan and Lakshmi R. Perumalsamy

Cancers 2023, 15(24), 5847; https://doi.org/10.3390/cancers15245847 - 14 Dec 2023

Cited by 3 | Viewed by 2171

Abstract

Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial–mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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12 pages, 1273 KiB

Open AccessReview

The Era of Immunotherapy in Hepatocellular Carcinoma: The New Mission and Challenges of Magnetic Resonance Imaging

by Yidi Chen, Chongtu Yang, Liuji Sheng, Hanyu Jiang and Bin Song

Cancers 2023, 15(19), 4677; https://doi.org/10.3390/cancers15194677 - 22 Sep 2023

Cited by 2 | Viewed by 1814

Abstract

In recent years, significant advancements in immunotherapy for hepatocellular carcinoma (HCC) have shown the potential to further improve the prognosis of patients with advanced HCC. However, in clinical practice, there is still a lack of effective biomarkers for identifying the patient who would benefit from immunotherapy and predicting the tumor response to immunotherapy. The immune microenvironment of HCC plays a crucial role in tumor development and drug responses. However, due to the complexity of immune microenvironment, currently, no single pathological or molecular biomarker can effectively predict tumor responses to immunotherapy. Magnetic resonance imaging (MRI) images provide rich biological information; existing studies suggest the feasibility of using MRI to assess the immune microenvironment of HCC and predict tumor responses to immunotherapy. Nevertheless, there are limitations, such as the suboptimal performance of conventional MRI sequences, incomplete feature extraction in previous deep learning methods, and limited interpretability. Further study needs to combine qualitative features, quantitative parameters, multi-omics characteristics related to the HCC immune microenvironment, and various deep learning techniques in multi-center research cohorts. Subsequently, efforts should also be undertaken to construct and validate a visual predictive tool of tumor response, and assess its predictive value for patient survival benefits. Additionally, future research endeavors must aim to provide an accurate, efficient, non-invasive, and highly interpretable method for predicting the effectiveness of immune therapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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22 pages, 1476 KiB

Open AccessReview

Radiolabeled NGR-Based Heterodimers for Angiogenesis Imaging: A Review of Preclinical Studies

by György Trencsényi, Gábor Halmos and Zita Képes

Cancers 2023, 15(18), 4459; https://doi.org/10.3390/cancers15184459 - 7 Sep 2023

Cited by 1 | Viewed by 1616

Abstract

Since angiogenesis/neoangiogenesis has a major role in tumor development, progression and metastatic spread, the establishment of angiogenesis-targeting imaging and therapeutic vectors is of utmost significance. Aminopeptidase N (APN/CD13) is a pivotal biomarker of angiogenic processes abundantly expressed on the cell surface of active vascular endothelial and various neoplastic cells, constituting a valuable target for cancer diagnostics and therapy. Since the asparagine–glycine–arginine (NGR) sequence has been shown to colocalize with APN/CD13, the research interest in NGR-peptide-mediated vascular targeting is steadily growing. Earlier preclinical experiments have already demonstrated the imaging and therapeutic feasibility of NGR-based probes labeled with different positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radionuclides, including Gallium-68 (⁶⁸Ga), Copper-64 (⁶⁴Cu), Technetium-99m (^99mTc), Lutetium-177 (¹⁷⁷Lu), Rhenium-188 (¹⁸⁸Re) or Bismuth-213 (²¹³Bi). To improve the tumor binding affinity and the retention time of single-receptor targeting peptides, NGR motifs containing heterodimers have been introduced to identify multi-receptor overexpressing malignancies. Preclinical studies with various tumor-bearing experimental animals provide useful tools for the investigation of the in vivo imaging behavior of NGR-based heterobivalent ligands. Herein, we review the reported preclinical achievements on NGR heterodimers that could be highly relevant for the development of further target-specific multivalent compounds in diagnostic and therapeutic settings. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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23 pages, 1396 KiB

Open AccessReview

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

by Davide Gnocchi, Dragana Nikolic, Rosa Rita Paparella, Carlo Sabbà and Antonio Mazzocca

Cancers 2023, 15(15), 3942; https://doi.org/10.3390/cancers15153942 - 3 Aug 2023

Cited by 7 | Viewed by 2202

Abstract

Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic–Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells “revert” to “primitive” characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells’ metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a “shift” toward “atavistic” biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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32 pages, 4111 KiB

Open AccessReview

Metabolites and Immune Response in Tumor Microenvironments

by Salvatore Cortellino and Valter D. Longo

Cancers 2023, 15(15), 3898; https://doi.org/10.3390/cancers15153898 - 31 Jul 2023

Cited by 8 | Viewed by 2487

Abstract

The remodeled cancer cell metabolism affects the tumor microenvironment and promotes an immunosuppressive state by changing the levels of macro- and micronutrients and by releasing hormones and cytokines that recruit immunosuppressive immune cells. Novel dietary interventions such as amino acid restriction and periodic fasting mimicking diets can prevent or dampen the formation of an immunosuppressive microenvironment by acting systemically on the release of hormones and growth factors, inhibiting the release of proinflammatory cytokines, and remodeling the tumor vasculature and extracellular matrix. Here, we discuss the latest research on the effects of these therapeutic interventions on immunometabolism and tumor immune response and future scenarios pertaining to how dietary interventions could contribute to cancer therapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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38 pages, 1655 KiB

Open AccessReview

Macrophage-Based Therapeutic Strategies in Hematologic Malignancies

by Saeed Khalili, Fatemeh Zeinali, Atousa Moghadam Fard, Seyed Reza Taha, Andarz Fazlollahpour Naghibi, Kimia Bagheri, Mahdieh Shariat Zadeh, Yeghaneh Eslami, Khashayar Fattah, Naghmeh Asadimanesh, Armin Azarimatin, Bahman Khalesi, Faezeh Almasi and Zahra Payandeh

Cancers 2023, 15(14), 3722; https://doi.org/10.3390/cancers15143722 - 22 Jul 2023

Cited by 1 | Viewed by 2356

Abstract

Macrophages are types of immune cells, with ambivalent functions in tumor growth, which depend on the specific environment in which they reside. Tumor-associated macrophages (TAMs) are a diverse population of immunosuppressive myeloid cells that play significant roles in several malignancies. TAM infiltration in malignancies has been linked to a poor prognosis and limited response to treatments, including those using checkpoint inhibitors. Understanding the precise mechanisms through which macrophages contribute to tumor growth is an active area of research as targeting these cells may offer potential therapeutic approaches for cancer treatment. Numerous investigations have focused on anti-TAM-based methods that try to eliminate, rewire, or target the functional mediators released by these cells. Considering the importance of these strategies in the reversion of tumor resistance to conventional therapies and immune modulatory vaccination could be an appealing approach for the immunosuppressive targeting of myeloid cells in the tumor microenvironment (TME). The combination of reprogramming and TAM depletion is a special feature of this approach compared to other clinical strategies. Thus, the present review aims to comprehensively overview the pleiotropic activities of TAMs and their involvement in various stages of cancer development as a potent drug target, with a focus on hematologic tumors. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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20 pages, 1599 KiB

Open AccessReview

Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

by Puja Bhattacharyya, Richard I. Christopherson, Kristen K. Skarratt, Jake Z. Chen, Thomas Balle and Stephen J. Fuller

Cancers 2023, 15(11), 2881; https://doi.org/10.3390/cancers15112881 - 23 May 2023

Cited by 1 | Viewed by 3650

Abstract

B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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11 pages, 1182 KiB

Open AccessHypothesis

A New Hypothesis Describing the Pathogenesis of Oral Mucosal Injury Associated with the Mammalian Target of Rapamycin (mTOR) Inhibitors

by Stephen T. Sonis and Alessandro Villa

Cancers 2024, 16(1), 68; https://doi.org/10.3390/cancers16010068 - 22 Dec 2023

Viewed by 1900

Abstract

It has been 24 years since rapamycin (sirolimus) was approved to mitigate solid organ transplant rejection and 16 years since mTOR (mammalian/mechanistic target of rapamycin) inhibitors reached patients as a cancer therapy. While the clinical benefits of mTOR inhibitors (mTORi) are robust, so too are their toxicities. Among the most common issues is the development of ulcers of the oral mucosa (mTOR-inhibitor associated stomatitis; mIAS). These lesions are distinct from those of other anti-cancer agents, occur with regularity, and impact patient outcomes. mIAS’ pathogenesis has been the subject of speculation, and its similar presentation to recurrent aphthous stomatitis (RAS) has led to the hypothesis that it might serve as a surrogate to better understand RAS. Based on a review of the literature, the current manuscript provides a hypothesis regarding the mechanisms by which mTORis uniquely initiate mucosal injury and an explanation for the observation that steroids (also an immunosuppressive) are effective in its treatment through a non-immunologic mechanism. Unexplained unique features of mIAS are discussed in this review in the context of future investigation. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Treatment Resistance)

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