At the occasion of the Breast Cancer Awareness Month, we would like to highlight the role of the interplay between the extracellular environment and the Cancer-Associated Fibroblasts (CAFs) on the tumoral development, including breast cancers.
In our previous articles, we described the pro-tumoral effect of the extracellular environment. Moreover, an increased rigidity of the environment can lead to the generation of activated fibroblasts that are called myofibroblasts or CAFs in the case of cancer.
In physiological conditions, myofibroblasts are activated following a wound. They secrete growth factors and extracellular matrix (ECM) components to heal the wound. They undergo apoptosis afterwards. But in the case of cancer, they are chronically activated. They still secrete ECM components leading to a fibrosis in the tissue. They also influence tumor cells by stimulating their growth and migration. They modulate immune cells by secreting cytokines. They also favor cell stemness and alter the vascular system. This, in combination with the increased extracellular environment stiffness, they lead to a lower accessibility of drugs to the tumor and thus a resistance to treatments.
In order to study these CAFs, scientists are looking for markers. However, CAFs are composed of a very heterogeneous population. In breast cancer, CAFs can have multiple origins: intralobular fibroblasts, interlobular fibroblasts, Mesenchymal Stem Cells in particular from the adipose tissue etc. Several markers are studied like α-Smooth Muscle Actin, Fibroblast-Specific Protein 1, Fibroblast Activation Protein, desmin, etc. But none of these markers is specific. Furthermore, it has been shown that CAFs have different functions and implications in drug resistance, according to their molecular profile.
Despite that, CAFs are still an interesting target for cancer treatment. For instance, Cazet et al. have shown in a triple negative breast cancer model that Hedgehog-dependent CAF activation and remodeling of the ECM promotes cancer stem cell niche via secretion of FGF5. This pathway is involved in docetaxel resistance. They propose to target this pathway and have shown good results in preclinical models, which has led to a clinical trial using Sonidegib in combination with Docetaxel.
The importance of CAFs and ECM in cancer highlights the need for relevant in vitro for selecting anticancer drug candidats. In this endeavor, HCS Pharma can provide you with BIOMIMESYS® matrices: they mimic the in vivo tumoral ECM composition and stiffness, and they allow to cocultivate cells (e.g. cancer cells and fibroblasts). For more information, please feel free to contact us.
Below are some articles about importance of CAFs in breast cancer:
Brechbuhl et al 2017. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin Cancer Res. 23(7): 1710–1721. doi:10.1158/1078-0432.CCR-15-2851.
Busch et al 2017. Cellular organization and molecular differentiation model of breast CAF. Molecular Cancer 16:73, doi: 10.1186/s12943-017-0642-7.
Cazet et al 2018. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nature Communications 9:2897. doi: 10.1038/s41467-018-05220-6
Houthuijzen & Jonkers 2018. CAF as Key Regulators of the Breast Cancer Tumor Microenvironment. Cancer and Metastasis Reviews. doi: 10.1007/s10555-018-9768-3.
Marusyk et al 2016. Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes. Cancer Research 76: 6495-6506 . doi: 10.1158/0008-5472.CAN-16-1457.
Tchou et al. 2012. Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Medical Genomics 6;5:39. doi: 10.1186/1755-8794-5-39.
Weber et al 2015. Osteopontin mediates an MZF1–TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene 34: 4821–4833. doi: 10.1038/onc.2014.410.