TGFBI modulates tumour hypoxia and promotes breast cancer metastasis

Abstract

Breast cancer metastasis is a complex process that depends on intrinsic characteristics of metastatic stem cells, but also on the particular microenvironment that supports their growth and modulates the plasticity of the system. In search for microenvironmental factors supporting cancer stem cell (CSC) growth and tumour progression to metastasis, we here investigated the role of the matricellular protein Transforming Growth Factor Beta Induced (TGFBI) in breast cancer. We crossed the MMTV-PyMT model of mammary gland tumourigenesis with a Tgfbi / mouse, and studied the CSC content of the tumours. We performed RNAseq on wt and ko tumours, and analysed the tumour vasculature and the immune compartment by IHC and FACS. The source of TGFBI expression was determined by qPCR and by bone marrow transplantation experiments. Finally, we performed in silico analyses using the METABRIC cohort to assess the potential prognostic value of TGFBI. We observed that deletion of Tgfbi led to a dramatic decrease in CSC content and lung metastasis. Our results show that lack of TGFBI resulted in tumour vessel normalisation, with improved vessel perfusion and decreased hypoxia, a major factor controlling CSCs and metastasis. Furthermore, human data

Stromal Protein-Mediated Immune Regulation in Digestive Cancers

“…We showed that this matricellular protein has immunosuppressive properties in an autoimmune context [ 170 ]. Also, in their recent study Fico and Santamaria-Martínez demonstrated that βig-h3 promotes breast cancer metastasis and plays an important role in tumor angiogenesis [ 171 ]. Moreover, employing a KO model of βig-h3 as well as in silico analysis of human breast cancer samples, they showed that βig-h3 overexpression is positively linked with tumor hypoxia and M2 macrophages but negatively associated with CD8+ T cell infiltration [ 171 ].…”

“…Also, in their recent study Fico and Santamaria-Martínez demonstrated that βig-h3 promotes breast cancer metastasis and plays an important role in tumor angiogenesis [ 171 ]. Moreover, employing a KO model of βig-h3 as well as in silico analysis of human breast cancer samples, they showed that βig-h3 overexpression is positively linked with tumor hypoxia and M2 macrophages but negatively associated with CD8+ T cell infiltration [ 171 ]. In fibrosis and wound healing, macrophage-derived βig-h3 that is released after the uptake of apoptotic cells is considered to control collagen turnover as shown in a study from Nacu et al [ 172 ].…”

Extracellular Vesicles in Tumors: A Potential Mediator of Bone Metastasis

“…Bone tissue is one of the most common sites for metastases in patients with advanced breast cancer, and the metastatic ratio is much higher than that of the liver, lung, and kidney ( Park et al, 2020 ; Zhang D. et al, 2020 ). Breast cancer metastasis to bones not only affects patient quality of life but also results in anemia, fractures, paraplegia, hypercalcemia, pain, cachexia, and increased mortality ( Fico and Santamaria-Martinez, 2020 ). When breast tumors metastasize to bone, the balance between osteoblasts and osteoclasts is damaged.…”

The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity

“…As happens with other components of the TME, certain components of the ECM have been proposed to have prognostic value in breast cancer. These include hyaluronan [ 166 , 167 ], asporin [ 168 , 169 ], syndecans [ 170 , 171 ], versican [ 172 , 173 ], collagens [ 174 , 175 ], fibronectin [ 174 , 176 ], transforming growth factor beta-induced (TGFBI) [ 177 ], osteopontin (OPN) [ 178 , 179 ], POSTN [ 180 , 181 ], laminins [ 174 , 182 , 183 ], and tenascin C (TNC) [ 172 , 174 , 184 ].…”

“…TGFBI, a POSTN paralog, is a 683 aminoacid ECM protein, which contains a secretory signal sequence, an N-terminal cysteine-rich domain (EMI), four fasciclin-1 (FAS1) domains, and an RGD (Arg-Gly-Asp) integrin binding site at the C-terminal end. We have recently identified TGFBI as a novel prognostic factor in BC and a crucial player in modulating interactions between tumor cells and the microenvironment: depletion of TGFBI reduces tumor hypoxia and normalizes the vasculature, thus dramatically decreasing CSC numbers and ultimately impairing metastasis formation [ 177 ]. The matricellular phosphoglycoprotein OPN has been shown to trigger the tumorsphere formation of ALDH high CD44 + CD24 − BC cells and to boost their metastatic behavior through the interaction with CD44 and RGD-dependent cell surface integrins [ 205 ].…”