Implication of Tumor Microenvironment in Chemoresistance: Tumor-Associated Stromal Cells Protect Tumor Cells from Cell Death

Abstract

Tumor development principally occurs following the accumulation of genetic and epigenetic alterations in tumor cells. These changes pave the way for the transformation of chemosensitive cells to chemoresistant ones by influencing the uptake, metabolism, or export of drugs at the cellular level. Numerous reports have revealed the complexity of tumors and their microenvironment with tumor cells located within a heterogeneous population of stromal cells. These stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) could be involved in the chemoresistance that is acquired by tumor cells via several mechanisms: (i) cell–cell and cell–matrix interactions influencing the cancer cell sensitivity to apoptosis; (ii) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells); (iii) direct cell-cell interactions with tumor cells (crosstalk or oncologic trogocytosis); (iv) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance; or (v) conversion of the cancer cells to cancer-initiating cells or cancer stem cells. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxins and physiological mediators of cell death.

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

“…There are recent findings that MSCs can be involved in the drug resistance development due to the release of various factors in the neighborhood of tumors [139][140][141][142][143]. Kurtova et al reported that MSCs protect chronic lymphocytic leukaemic cells from apoptosis induced by fludarabine, dexamethosone, and cyclophosphamide [125].…”

Exosomes: Emerging Players of Intercellular Communication in Tumor Microenvironment

“…), as well as extracellular matrix which encircle all tumor cells, and soluble factors such as growth factors, chemokines and cytokines. 61 Besides genetic and epigenetic control, cells of the TME also possess a remodelling influence on the tumor growth and its transformation from benign to malignant. For tumor propagation, cellular communication is not only required between the tumor cells but also between cancer cells and the other neighbouring cells in TME.…”

Microenvironment–A Role in Tumour Progression and Prognosis

“…The use of two angiogenic inhibitors like VEGFR2 inhibitor and PDGFR-β together has shown very promising results in a glioma model. They target the pericytes and endothelial cells causes diminish vascular supply to the tumour [15].…”

“…They interact with carcinoma cells and inflammatory cells, providing factors for reciprocal signaling loops. TAFs has been implicated to express growth factors like Epidermal Growh Factor (EGF) and transforming growth factor (TGF), Hepatocyte Growth Factor (HGF), and FGF causes carcinoma cell proliferation [15].…”