Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

Abstract

Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME.

Keywords: anticancer drugs; cancer stem cells; chemoresistance; targeted therapy; tumor microenvironment.

Figure 1

Crosstalk between cancer stem cells (CSCs) and tumor microenvironment (TME) components. Within the tumor mass, a subpopulation of cancer cells, called cancer stem cells (CSCs), are endowed with high resistance to anticancer therapies, due to elevated expression levels of ABC transporters, anti-apoptotic proteins and a proficient DNA damage repair (DDR) machinery. Tumor microenvironment (TME), mainly composed by cancer associated fibroblasts (CAFs), adipocytes, immune and endothelial cells, has a key role in the maintenance of CSC peculiarities. Cytokines and chemokines produced by both CSCs and TME cells boost cancer cell growth, prompt chemoresistance and promote tumor progression and relapse.