Targeting the Interplay Between Cancer Fibroblasts, Mesenchymal Stem Cells, and Cancer Stem Cells in Desmoplastic Cancers

Abstract

Malignant tumors are highly heterogeneous and likely contain a subset of cancer cells termed cancer stem cells (CSCs). CSCs exist in a dynamic equilibrium with their microenvironments and the CSC phenotype is tightly regulated by both cell-intrinsic and cell-extrinsic factors including those derived from their surrounding cells or stroma. Many human solid tumors like breast, lung, colorectal and pancreatic cancers are characterized by a pronounced stromal reaction termed "the desmoplastic response." Carcinoma-associated fibroblasts (CAFs) derived either from resident fibroblasts or tumor-infiltrating mesenchymal stem cells (MSCs) are a major component of the stroma in desmoplastic cancers. Recent studies identified subpopulations of CAFs proficient in secreting a plethora of factors to foster CSCs, tumor growth, and invasion. In addition, cytotoxic therapy can lead to the enrichment of functionally perturbed CAFs, which are endowed with additional capabilities to enhance cancer stemness, leading to treatment resistance and tumor aggressiveness. When recruited into the tumor stroma, bone-marrow-derived MSCs can promote cancer stemness by secreting a specific set of paracrine factors or converting into pro-stemness CAFs. Thus, blockade of the crosstalk of pro-stemness CAFs and MSCs with CSCs may provide a new avenue to improving the therapeutic outcome of desmoplastic tumors. This up-to-date, in-depth and balanced review describes the recent progress in understanding the pro-stemness roles of CAFs and tumor-infiltrating MSCs and the associated paracrine signaling processes. We emphasize the effects of systemic chemotherapy on the CAF/MSC-CSC interplay. We summarize various promising and novel approaches in mitigating the stimulatory effect of CAFs or MSCs on CSCs that have shown efficacies in preclinical models of desmoplastic tumors and highlight the unique advantages of CAF- or MSC-targeted therapies. We also discuss potential challenges in the clinical development of CSC- or MSC-targeted therapies and propose CAF-related biomarkers that can guide the next-generation clinical studies.

Keywords: cancer stem cells; cancer-associated fibroblasts; desmoplasia; mesenchymal stem cells; paracrine signaling.

Figure 1

The pro-stemness functions of CAFs and tumor infiltrating MSCs linked to their different functional and treatment status. CAFs, especially their pro-stemness subset, secrete assorted cytokine and chemokines, including IL-6, IL-8, LIF, PGE-2, CXCL-1, CXCL-12, HGF, and TGF-β through heightened STAT, and NF-κB signaling activity to promote the reprogramming of cancer cells into CSCs and/or directly expand the CSC population. CAFs also secret Nodal and osteopontin (OPN) to promote CSCs. Cytotoxic therapies such as chemotherapy (C/T) and ionizing radiation (IR) further potentiate the pro-stemness functions of CAFs by further activating STAT-1 and NF-κB signaling, thereby inducing the secretion of a different panel of pro-stemness factors, including ELR⁺-CXCL chemokines, and Wnt-16B. Bone marrow-derived and tumor-infiltrating MSCs can promote CSCs by converting into CAFs or by secreting several pro-stemness chemokines such as IL-6, CCL-5, PGE-2, and JAG-1. C/T-educated MSCs further secrete the pro-stemness chemokine CXCL-10 by activating STAT-1 signaling. The reference numbers are shown in blue.

Figure 2

A multitude of approaches to block the CAF/MSC–CSC crosstalk. Function-blocking antibodies, including α-IL-6, α-IL-8, α-LIF, α-CCL-2, and α-CCL5, or small molecular inhibitors, such as the TGF-β inhibitor SD208, can be used to block the stimulatory effect of these pro-stemness factors secreted by CAFs or C/T-modulated CAFs. On the other hand, the CAF-CSC paracrine signaling can be blocked by function-blocking antibodies (e.g., α-CXCR-1, α-CXCR-2) or small molecule inhibitors (e.g., repertaxin, AZ13381758, SB431542) of the receptors on CSCs and/or cancer cells. Likewise, the pro-stemness functions of tumor-infiltrating MSCs can be antagonized by function-blocking antibodies against IL-6 or CCL-5. The enhanced pro-stemness functions of C/T-modulated CAFs or MSCs can be potentially blocked by function-blocking anti-ELR⁺-CXCL-chemokine antibodies, anti-CXCL-10 antibody, the CXCL-10 inhibitor AMG-478 (encapsulated by MSC-derived nano-ghost, NG), or adopting low-dose metronomic (LDM) C/T regimens. Function-blocking α-GRP-77 antibodies can be used to reduce the tumor infiltration of CD10⁺GPR-77⁺ pro-stemness CAFs. Calcipotriol can activate VDR signaling to inhibit IL-6, CCL-2, and CXCL-1 production by CAFs. Finally, FAP⁺ or GPR-77⁺ CAFs can be depleted by using DNA vaccines to induce CAF-specific tumor-infiltrating T cells (TILs) or administrating CAF-specific CAR-T cell or other types of engineered immune cells. The reference numbers are shown in blue.