Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways

Abstract

Accumulating evidence indicates that intratumoral heterogeneity contributes to the development of resistance to anticancer therapeutics. Fibroblasts, which are components of the paraneoplastic stroma, play a crucial role in the wound-healing process. Activated fibroblasts accumulate in the wound and are involved in many aspects of the tissue remodeling cascade that initiates the repair process and prevents further tissue damage. The pathophysiological roles of cancer-associated fibroblasts (CAFs) in the heterogeneous tumor microenvironment have attracted increasing interest. CAFs play crucial roles in tumor progression and the response to chemotherapy. Several cytokines and chemokines are involved in the conversion of normal fibroblasts into CAFs, and some of these form a feedback loop between cancer cells and CAFs. In addition, the physical force between tumor cells and CAFs promotes cooperative invasion or co-migration of both types of cells. Pro-inflammatory cytokines, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), are secreted by both cancer cells and CAFs, and mediate the epigenetic modification of CAFs. This enhances the pro-tumorigenic function of CAFs mediated by promoting actomyosin contractility and extracellular matrix remodeling to form the tracks used for collective cancer cell migration. The concept of intra-tumoral CAF heterogeneity refers to the presence of inflammatory CAFs with low levels of α-smooth muscle actin (α-SMA) and high levels of IL-6 expression, which are in striking contrast to transforming growth factor-β (TGF-β)-dependent myofibroblastic CAFs with high α-SMA expression levels. CAF populations that suppress tumor growth and progression through stroma-specific Hedgehog (Hh) activation have been detected in different murine tumor models including those of the bladder, colon, and pancreas. A new therapeutic strategy targeting CAFs is the "stromal switch," in which tumor-promoting CAFs are changed into tumor-retarding CAFs with attenuated stromal stiffness. Several molecular mechanisms that can be exploited to design personalized anticancer therapies targeting CAFs remain to be elucidated. Strategies aimed at targeting the tumor stroma as well as tumor cells themselves have attracted academic attention for their application in precision medicine. This novel review discusses the role of the activation of EGFR, Wnt/β-catenin, Hippo, TGF-β, and JAK/STAT cascades in CAFs in relation to the chemoresistance and invasive/metastatic behavior of cancer cells. For instance, although activated EGFR signaling contributes to collective cell migration in cooperation with CAFs, an activated Hippo pathway is responsible for stromal stiffness resulting in the collapse of neoplastic blood vessels. Therefore, identifying the signaling pathways that are activated under specific conditions is crucial for precision medicine.

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

“…Thus, whilst naïve SFs display hypermethylation of the promoter and TSS regions of genes associated with regulation of pluripotency and (oncofetal) development, many of these sites are hypomethylated and potentially derepressed in CIA-, but not ES-62-CIA-, SFs. By contrast, whilst elements associated with the FoxO, Hippo and Wnt signalling pathways that are key to the regulation of these processes (stem cell biology, cilia and intercellular communication, organ development, immunomodulation, tissue repair and regeneration and ageing 64, 84, 85 ) are similarly hypomethylated in CIA SFs and hypermethylated in ES-62-CIA, these genes are also hypomethylated in naïve SFs. Of related interest, we have previously shown ES-62 to strongly induce negative regulators (WIF1, AMOTL2 and CRYBB2) of Wnt signalling in RA synovial membranes, in vitro 86 .…”

Cancer-associated adipocytes: emerging supporters in breast cancer

“…By constructing a 3D collagen invasion model, Wei et al showed that CAAs remodeled collagen alignment concerning of PAI-1 or PLOD2 up-regulation during crosstalk with BC cells in vitro and in vivo, further boosting BC metastasis [80]. It is worth noting that the increased matrix stiffness, which can be sensed by many cell types, is a feature of most solid tumors [86]. Yes-associated protein (YAP) function is essential to establish and maintain the tumor-promoting function of CAFs, including stromal sclerosis, invasion and angiogenesis.…”

“…It has been reported that the Hippo pathway can be activated by stromal stiffness in solid tumor tissues, and central to this signaling is a kinase cascade leading from the tumor suppressor Hippo to the oncogenic Yki (YAP/TAZ in mammals), which is a transcriptional coactivator of target genes involved in cell proliferation and survival [88]. In addition, YAP is activated in CAFs in response to mechanical stress, perturbation of the actin cytoskeleton and ECM stiffness [86,87]. Besides, the increased expression of YAP in preadipocytes is correlated with the repression of adipogenic differentiation processes [89].…”

Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

“…The PLX4720 has an effect on the tumor stroma and promote matrix production, ECM remodeling leading to activation of integrin β1/focal adhesion kinase (FAK)/Src and ERK signaling. Melanoma-associated fibroblasts activate paradoxically adhesion-mediated signaling, which supports residual disease, result in enhancing the population of cancer cells [20,58,59]. Activating mutations in kinase PI3K/AKT have been reported that increase AKT activity, promoting melanoma and resistance to apoptosis [60].…”

“…EndMT contributes to the accumulation of CAFs and most CAFs are formed by EndMT [18]. For example, with regard to the omental tumor microenvironment, omental fibroblasts are trans-differentiated from adipose-derived mesenchymal stem cells by ovarian cancer-derived exosomes and are associated with transforming growth factor beta (TGF-β) signaling secreted by both cancer cells and stromal cells [19,20]. TGF-β contributes to recruiting stromal cell types characterized by CAFs, inducing ECM production and downregulating the expression of ECM-associated protease [21].…”