Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy

Abstract

Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue “niche”, cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.

Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases

“…This resistance can be the result of different mechanisms due to genetic or phenotypic changes termed intrinsic resistance or to extrinsic resistance involving the effect of the tumor microenvironment (TME) [ 136 ]. In the TME, endothelial cells, fibroblasts and immune cells interact to support tumor growth and progression, where homotypic or heterotypic exosome transfers are regarded as potent effectors [ 136 , 137 , 138 ].…”

“…Cancer-associated fibroblasts (CAFs), which are largely regarded as the principal component of tumors and supportive cells, provide a nursing niche and actively regulate the survival and proliferation of cancer cells [ 137 , 138 ]. CAFs affect cross-interactions between the stroma and tumor to activate tumor-supportive mechanisms [ 160 , 161 ].…”

“…Moreover, this EMT confers cell plasticity on CSCs and CAFs. However, CAFs and CAF-like phenotypes may release cancer-supportive signals after exposure to different chemotherapies, as well as to a single ablative dose of radiotherapy [ 138 , 161 , 169 ].…”

New Insights into Therapy-Induced Progression of Cancer

“…The major component of the tumor stroma is tumor-associated fibroblasts [220]. Communication between CAFs and tumor cells promotes the formation of a therapy-resistant phenotype in the latter [221]. For example, CAFs have been associated with the development of resistance to gemcitabine in pancreatic cancer through secretion of miRNA-106b [222]; to gefitinib in non-small cell lung cancer via secretion of IGF-1 and HGF [223]; to 5-fluorouracil in colorectal cancer [224]; to cisplatin in esophageal squamous cell cancer through secretion of PAI-1 [225] and TGFβ1 [226], in gastric cancer through secretion of miR-522 [227], IL-11, IL-6, and other cytokines and growth factors [228], and in lung adenocarcinoma due to secretion of IL-11 [229].…”

CRISPR/Cas9 Genome Editing vs. Over-Expression for Fluorescent Extracellular Vesicle-Labeling: A Quantitative Analysis

“…A myriad of cell types, including epithelial, endothelial, blood, stem, and tumor cells release small vesicles into their extracellular milieu [ 1 , 2 , 3 , 4 ]. These vesicles contain transmembrane and soluble proteins [ 5 , 6 , 7 ], RNA [ 8 ], and DNA [ 9 ] molecules, which are membrane-enclosed and protected from extracellular proteases and nucleases.…”