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The Structural-Functional Rationale for Targeting the Tumor Microenvironment
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The Structural-Functional Rationale for Targeting the Tumor Microenvironment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 16058

Special Issue Editor

Prof. Dr. Roberto Perris

E-Mail Website
Guest Editor
COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
Interests: extracellular matrix; proteoglycans; immunotherapy; metastasis; angiogenesis; cell-matrix interactions; cancer stem cells; cell migration/invasion; tumour microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the first observation of a defined “tumor stroma” in the transplantation experiments of the late 1950s, and the incipient suspicion that this non-neoplastic compartment could influence the progression of the disease, virtually everything has changed regarding how we now perceive the importance of this space-filling cellular and acellular material of the lesion, broadly known as the tumor microenvironment (TME). It emerges that the TME is a highly dynamic structure encompassing a multitude of plastic cell phenotypes undergoing bidirectional genetic reprogramming and complex reciprocal interplays entailing interactions with infiltrating and resident immune cells. It has recently been discovered that these interplays are entertained through sophisticated means of short- and long-range communication, in part purported through the exchange of microvesicles and the structuring of tunnelling nanotubes. Modulable cell rearrangements within the TME are associated with a constant remodeling of the extracellular matrix deposited by the cancer and TME cells jointly, to also allow for the differential retention of signaling molecules. Intrinsic and gradually acquired functional properties of the TME have been implicated in all facets of tumor development spanning from dormancy to metastasis formation, from neovascularization to drug resistance, and from immune escape to the segregation of genetically and phenotypically distinct cancer cell subsets. Cellular and molecular components of the TME are therefore attractive therapeutic targets, but a more profound knowledge of the cancer-specific, and possibly patient-elective, TME composition is needed to deepen our understanding of how the TME governs cancer biology and ways to effectively target it to halt tumor progression. This Special Issue aims to collect original research and review articles focusing on molecular advances in tumor microenvironment.

Prof. Dr. Roberto Perris
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 short 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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor microenvironment
  • cell communication
  • ECM remodelling
  • cell reprogramming
  • cancer progression
  • tumor stroma
  • metastasis formation
  • therapeutic targets

Published Papers (5 papers)

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Research

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19 pages, 4075 KiB  
Article
Resveratrol Modulates Chemosensitisation to 5-FU via β1-Integrin/HIF-1α Axis in CRC Tumor Microenvironment
by Aranka Brockmueller, Sosmitha Girisa, Ajaikumar B. Kunnumakkara and Mehdi Shakibaei
Int. J. Mol. Sci. 2023, 24(5), 4988; https://doi.org/10.3390/ijms24054988 - 5 Mar 2023
Cited by 15 | Viewed by 1780
Abstract
Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize β1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize [...] Read more.
Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize β1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize these receptors to overcome 5-FU chemoresistance in CRC cells has not yet been investigated. Effects of β1-integrin knockdown on anti-cancer capabilities of resveratrol and 5-FU were investigated in HCT-116 and 5-FU-resistant HCT-116R CRC tumor microenvironment (TME) with 3D-alginate as well as monolayer cultures. Resveratrol increased CRC cell sensitivity to 5-FU by reducing TME-promoted vitality, proliferation, colony formation, invasion tendency and mesenchymal phenotype including pro-migration pseudopodia. Furthermore, resveratrol impaired CRC cells in favor of more effective utilization of 5-FU by down-regulating TME-induced inflammation (NF-kB), vascularisation (VEGF, HIF-1α) and cancer stem cell production (CD44, CD133, ALDH1), while up-regulating apoptosis (caspase-3) that was previously inhibited by TME. These anti-cancer mechanisms of resveratrol were largely abolished by antisense oligonucleotides against β1-integrin (β1-ASO) in both CRC cell lines, indicating the particular importance of β1-integrin receptors for the 5-FU-chemosensitising effect of resveratrol. Lastly, co-immunoprecipitation tests showed that resveratrol targets and modulates the TME-associated β1-integrin/HIF-1α signaling axis in CRC cells. Our results suggest for the first time the utility of the β1-integrin/HIF-1α signaling axis related to chemosensitization and overcoming chemoresistance to 5-FU in CRC cells by resveratrol, underlining its potential supportive applications in CRC treatment. Full article
(This article belongs to the Special Issue The Structural-Functional Rationale for Targeting the Tumor Microenvironment)
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15 pages, 4419 KiB  
Article
Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma
by Pei-Wen Wang, Tung-Yi Lin, Pei-Ming Yang, Chau-Ting Yeh and Tai-Long Pan
Int. J. Mol. Sci. 2022, 23(18), 10777; https://doi.org/10.3390/ijms231810777 - 15 Sep 2022
Cited by 7 | Viewed by 2154
Abstract
Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently [...] Read more.
Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC. Full article
(This article belongs to the Special Issue The Structural-Functional Rationale for Targeting the Tumor Microenvironment)
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Review

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14 pages, 1709 KiB  
Review
The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma
by Cesar U. Monjaras-Avila, Ana C. Lorenzo-Leal, Ana C. Luque-Badillo, Ninadh D’Costa, Claudia Chavez-Muñoz and Horacio Bach
Int. J. Mol. Sci. 2023, 24(9), 7946; https://doi.org/10.3390/ijms24097946 - 27 Apr 2023
Cited by 14 | Viewed by 2996
Abstract
Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease. Full article
(This article belongs to the Special Issue The Structural-Functional Rationale for Targeting the Tumor Microenvironment)
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19 pages, 1795 KiB  
Review
Modulation of the Tumor Microenvironment by Microbiota-Derived Short-Chain Fatty Acids: Impact in Colorectal Cancer Therapy
by Sara Gomes, Ana Catarina Rodrigues, Valerio Pazienza and Ana Preto
Int. J. Mol. Sci. 2023, 24(6), 5069; https://doi.org/10.3390/ijms24065069 - 7 Mar 2023
Cited by 11 | Viewed by 6486
Abstract
Finding new therapeutic approaches towards colorectal cancer (CRC) is of increased relevance, as CRC is one of the most common cancers worldwide. CRC standard therapy includes surgery, chemotherapy, and radiotherapy, which may be used alone or in combination. The reported side effects and [...] Read more.
Finding new therapeutic approaches towards colorectal cancer (CRC) is of increased relevance, as CRC is one of the most common cancers worldwide. CRC standard therapy includes surgery, chemotherapy, and radiotherapy, which may be used alone or in combination. The reported side effects and acquired resistance associated with these strategies lead to an increasing need to search for new therapies with better efficacy and less toxicity. Several studies have demonstrated the antitumorigenic properties of microbiota-derived short-chain fatty acids (SCFAs). The tumor microenvironment is composed by non-cellular components, microbiota, and a great diversity of cells, such as immune cells. The influence of SCFAs on the different constituents of the tumor microenvironment is an important issue that should be taken into consideration, and to the best of our knowledge there is a lack of reviews on this subject. The tumor microenvironment is not only closely related to the growth and development of CRC but also affects the treatment and prognosis of the patients. Immunotherapy has emerged as a new hope, but, in CRC, it was found that only a small percentage of patients benefit from this treatment being closely dependent on the genetic background of the tumors. The aim of this review was to perform an up-to-date critical literature review on current knowledge regarding the effects of microbiota-derived SCFAs in the tumor microenvironment, particularly in the context of CRC and its impact in CRC therapeutic strategies. SCFAs, namely acetate, butyrate, and propionate, have the ability to modulate the tumor microenvironment in distinct ways. SCFAs promote immune cell differentiation, downregulate the expression of pro-inflammatory mediators, and restrict the tumor-induced angiogenesis. SCFAs also sustain the integrity of basement membranes and modulate the intestinal pH. CRC patients have lower concentrations of SCFAs than healthy individuals. Increasing the production of SCFAs through the manipulation of the gut microbiota could constitute an important therapeutic strategy towards CRC due to their antitumorigenic effect and ability of modulating tumor microenvironment. Full article
(This article belongs to the Special Issue The Structural-Functional Rationale for Targeting the Tumor Microenvironment)
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13 pages, 1217 KiB  
Review
The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance
by Vinicio Carloni, Elisa Morganti, Andrea Galli and Antonio Mazzocca
Int. J. Mol. Sci. 2023, 24(1), 245; https://doi.org/10.3390/ijms24010245 - 23 Dec 2022
Cited by 1 | Viewed by 2191
Abstract
Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary [...] Read more.
Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary mechanism. Recent efforts to understand DNA damage/chromosomal instability and elucidate its role in initiation or progression of cancer have also disclosed its vulnerabilities represented by inappropriate DNA damage response, chromatin changes, andinflammation. Understanding these vulnerabilities can provide important clues for predicting treatment response and for the development of novel strategies that prevent the emergence of therapy resistant tumors. Full article
(This article belongs to the Special Issue The Structural-Functional Rationale for Targeting the Tumor Microenvironment)
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