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.
