Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells

Abstract

Cancer cells recruit normal cells such as fibroblasts to establish reactive microenvironments. Via metabolic stress, catabolism and inflammation, these cancer-associated fibroblasts set up a synergistic relationship with tumour cells, that contributes to their malignancy and resistance to therapy. Given that chemotherapy is a systemic treatment, the possibility that healthy cell damage affects the metastatic risk or the prospect of developing a second malignancy becomes relevant. Here, we demonstrate that standard chemotherapies phenotypically and metabolically transform stromal fibroblasts into cancer-associated fibroblasts, leading to the emergence of a highly glycolytic, autophagic and pro-inflammatory microenvironment. This catabolic microenvironment, in turn, activates stemness (Sonic hedgehog/GLI signalling), antioxidant response and interferon-mediated signalling, in adjacent breast cancer cells. Thus, we propose a model by which chemotherapy-induced catabolism in healthy fibroblasts constitutes a source of energy-rich nutrients and inflammatory cytokines that would activate stemness in adjacent epithelial cells, possibly triggering new tumorigenic processes. In this context, immune cell recruitment would be also stimulated to further support malignancy.

Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells

“…The Cignal Lenti reporter assay (Luc) system (Qiagen) was chosen for monitoring HIF- and NFκB-Luc pathway activity in fibroblasts, as we previously described [46, 47]. Luciferase assay (E1501, Promega) was performed in luciferase reporter hTERT-BJ1 cells treated with atovaquone.…”

Targeting the tumour stroma to improve cancer therapy

“…In other in vitro studies, the addition of conditioned media from an immortalized fibroblast cell line to head and neck squamous cell carcinoma (HNSCC)-derived cells increased resistance to cisplatin two-fold relative to cells not treated with conditioned medium 233 . Along the same lines, chemotherapy can cause non-activated fibroblasts to develop a CAF-like phenotype, secreting factors that promote a stem-cell-like phenotype in breast cancer cells 234 . In a colon cancer model, a similar secretory phenotype was observed in fibroblasts treated with 5-fluorouracil or oxaliplatin, which induced a stem-cell-like, chemotherapy-resistant phenotype in cancer cells via a mechanism involving exosomes 235 .…”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…In turn, proliferating CAFs protect cancer cells against apoptosis by providing nutrients to cancer cells (Martinez-Outschoorn et al 2011b). Furthermore, standard chemotherapies transform phenotypically and metabolically characterized breast fibroblasts into CAFs, creating a hypoxic, glycolytic, autophagic, and proinflammatory microenvironment that in turn activates stemness through Sonic hedgehog (Shh)/GLI signaling, antioxidant response, and interferon-mediated signaling in breast cancer cells (Peiris-Pages et al 2015). Hypoxic senescent fibroblasts can promote prostate cancer aggressiveness by inducing EMT, secreting energyrich compounds to support cancer cell growth, promoting M2 macrophage polarization, and promoting angiogenesis through recruitment of BM-derived endothelial precursor cells and proliferation and invasion of mature endothelial cells .…”