The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

Abstract

Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor microenvironment components such as mesenchymal stem cells and the extracellular matrix.

Identification of gene modules associated with survival of diffuse large B-cell lymphoma treated with CHOP-based chemotherapy

“…Meanwhile, less drug resistance probability of three chemotherapeutic drugs (cyclophosphamide, doxorubicin, vincristine) was found with the increased expression of hub genes. Studies have found that effector T cells can abrogate stromal-mediated chemoresistance, which is vital for cancer cell resistance [47], by altering glutathione and cystine metabolism in fibroblasts [48], and the activation of T-cell immune response could reverse chemoresistance [49] in ovarian cancer. Similarly, melanoma related research has reported that chemosensitivity would be increased by activated CD4 + T cells [50].…”

Emerging role of exosome signalling in maintaining cancer stem cell dynamic equilibrium

“…Tumour microenvironment consisted of a variety of different cell populations including cancer cells, CSCs, mesenchymal stem cells (MSCs), endothelial cells, fibroblasts, bone marrow‐derived cells (BMDC), etc., and recent studies demonstrated that cells within tumour microenvironment can regulate cancer cell stemness phenotype, promote tumour cell invasion and metastasis, induce angiogenesis, and immune cell recruitment by secreting various bioactive factors, these factors were also involved with the conversion of non‐CSCs into CSCs. For example, high‐mobility group box 1 (HMGB1) released by cancer‐associated fibroblast (CAFs) was found to enhance stemness and tumorigenicity of breast cancer cells through HMGB1/TLR4 signalling pathway; CAFs‐derived HGF could activate FRA1/HEY1 signalling pathway to endow hepatocellular carcinoma cells with stemness phenotype .…”

Evidence of Tumour Microenvironment and Stromal Cellular Components in Retinoblastoma

“…The complex mechanisms of chemoresistance observed in tumour cells are now being attributed to the interactions occurring in the tumour microenvironment (TME) [12]. Components of TME comprising tumour cells, immune cells and other stromal cells along with their vital interactions contribute to treatment response and disease prognosis.…”