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

Gábor Valcz,Tibor Krenács,Péter Igaz,Edit I Buzás,Béla Molnár,Anna Sebestyén,Zoltán Szállási

doi:10.3390/cancers12082324

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.

Highlights

Darwin’s natural selection theory in ecosystems shares many similarities with the evolution of tumors considering that cancer cells can adapt to their ever-changing microenvironment affected by therapeutic interventions [1,2]
Chemotherapy-treated carcinoma-associated fibroblasts (CAFs)-released sEVs showed differential effects on the recipient cancer cells as compared to sEVs from untreated but resistant CAFs [83]. This supports the hypothesis that the cargo of therapy-induced extracellular vesicle (EV) is different from that of the non-therapy-induced ones [96]. These results suggest that CAF-derived sEVs do mediate protective/supportive signals against the therapeutic stress, but they dynamically control the size of the cancer stem cells (CSCs) pool by the dedifferentiation process
Anti-cancer therapies may act as double-edged swords. They may promote tumor evolution and progression though increasing the selection pressure on the surviving cells based on intratumoral heterogeneity

Summary

Introduction

Darwin’s natural selection theory in ecosystems shares many similarities with the evolution of tumors considering that cancer cells can adapt to their ever-changing microenvironment affected by therapeutic interventions [1,2]. Cells of minimal residual disease may develop through positive selection of newly mutated, resistant clones (clonal evolution hypothesis) They may originate from resistant cancer stem cells (CSCs), which lie at to the top of the tumor hierarchy (cancer stem cell hypothesis) [6,7,8]. These two models are not mutually exclusive and both may contribute to intratumoral heterogeneity [9]. Anti-cancer therapies can induce alarm signals in tumor-stroma interactions, which can select out cancer cells of CSC phenotypes, and activate cells in the adjacent stroma. Tumor-Stroma Co-Evolution Requires CAF Survival, Recruitment, and Differentiation

Therapy-Resistant Subpopulations of Carcinoma-Associated Fibroblasts

Treatment-Related Replenishment of CAFs

Differential Cellular Behavior of Resting and Chemotherapy-Treated CAFs

Extracellular Vesicle-Mediated Resistance at the Tumor Cell-CAF Interface

Conclusions