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

Miriam Gaggianesi,Matilde Todaro,Lorenzo Colarossi,Giuseppe Pistone,Naida Faldetta,Francesco Verona,Caterina D'Accardo,Giorgio Stassi,Veronica Veschi,Gaetana Porcelli,Vincenzo Davide Pantina,Simone Di Franco,Maria Rita Bongiorno

doi:10.3389/fonc.2021.702642

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.

Highlights

Despite huge progress has been made in the development and optimization of anti-tumor therapies, cancer remains the second leading cause of death worldwide
Among the variety of cytokines and growth factors secreted by cancer-associated fibroblasts (CAFs), a great number of studies highlighted the IL-6 and IL-8 essential role in the maintenance of stem-like features of cancer cells and in the promotion of tumor growth, metastasis formation, and chemoresistance [93, 94]
Compelling evidence highlights that the inefficacy of anti-cancer therapy results from the refractoriness of a subpopulation of tumor cells, called cancer stem cells (CSCs), which are endowed with stem-like features including tumorinitiating and metastasis formation capabilities

Summary

Introduction

Despite huge progress has been made in the development and optimization of anti-tumor therapies, cancer remains the second leading cause of death worldwide. Invasive CD133+ stem-like cells isolated from pancreatic cancer cell lines displayed higher expression levels of gene involved in the BRCA1-mediated DNA repair pathway and resistance to gemcitabine (GEM) treatment compared to CD133subpopulation [65]. SDF-1 interacting with its receptor (CXCR4), highly expressed on CSC surface, regulated stem phenotype through the activation of Wnt/b-catenin and PI3K/AKT signaling pathways and boosted the proliferation of CD44+/ CD24- BC cells [92].

Results

Conclusion