Fibroblaste

Un fibroblaste est une cellule présente dans le tissu conjonctif ; elle est parfois appelée cellule de soutien. Ce sont notamment des cellules résidentes du derme qui en assurent la cohérence et la souplesse. Elle sécrète des protéoglycanes et des glycoprotéines. Description vignette|gauche|Fibroblastes

Forme de la cellule : fusiforme ou étoilée, aplatie et allongée
Taille : longue de et large de
Noyau : ovale, il contient de la chromatine peu condensée (en motte périphérique) et un appareil de Golgi qui lui est périphérique
Cytoplasme : il est riche en réticulum endoplasmique rugueux (RER), ribosomes libres et mitochondries. De plus, elle contient un réseau de micro-filaments d'actine et de vimentine qui constitue le cytosquelette (particulièrement développé dans les fibroblastes) On observe à la surface des fibroblastes des récepteurs aux lipoprotéines de basse densité (LDL) et aux lipoprotéines de haute densité (HDL).

Rôle Le fibroblaste a pl

The role of recruited bone-marrow derived mesenchymal stem cells in the establishment of the tumor stroma and a growth-supportive environment

Jean-Paul Abbühl

The Mesenchymal Stem Cell (MSC) is a self-renewing multipotent progenitor originally found in the bone marrow. It has drawn strong interest from translational research because of the multipotency of MSCs, their immunosuppression, their intrinsic homing and their promotion of wound healing in human patients. Currently available methods rely on in vitro culture for the isolation and expansion of MSCs and most studies used these cells for their investigation. Fibroblasts constitute the connective tissue and support epithelial or hematopoietic cells. Although they have already been extensively investigated, it is not clear whether stem cells exist in vivo which specifically regenerate fibroblasts. MSCs are a potential candidate, because of their fibroblastic shape in vitro, their differentiation towards several mesodermal lineages and their supportive function. We aim to characterize the in vivo differentiation potential of MSCs toward fibroblasts in normal and tumor tissues. A new transplantation approach was developed in order to transfer labeled MSCs in the bone marrow and assess their recruitment and lineage contribution in vivo. Long-term engraftment was accomplished by isolating and transplanting these cells within one day. To this end, strategies for their purification, preconditioning of the host and transplantation methodologies were established during this thesis. We were able to enrich MSCs over 1000 fold by combining a new extraction protocol, a negative selection by MACS and a positive selection by FACS. Cloning of sorted MSCs was performed to confirm their multipotency at single cell level. GFP-expressing MSCs were able to engraft in host mice tolerant for GFP and their expansion in vivo was stimulated by block of GSK3 activity. Altogether, the chimeric MSC model was used to track the recruitment of bone-marrow derived MSCs into spontaneous breast tumors. The tumor microenvironment encompasses several non-tumorigenic cells interacting with cancer cells. Among them, cancer-associated fibroblasts are known to participate in carcinogenesis. Whilst this heterogeneous stromal population has been extensively investigated, their source(s) remain elusive. I now propose tumoral MSCs as one source of cancer-associated fibroblast, based on their ability to self-renew and reconstitute stromal heterogeneity upon serial transplantation. Finally, I introduced the new concept that the multipotency of MSCs is subjugated by cancer cells to meet their requirements for enhanced tumor progression and prepare for metastasis. I found MSCs present in the tumor microenvironment to differentiate into cancer-associated osteoblasts and produce hydroxyapatite-mineralization in vivo. Microcalcification is an accepted poor prognostic feature in breast cancer patients but its function and origin is not documented. I showed that hydroxyapatite was able to promote proliferation of tumor cells and increased intracellular calcium concentration. Lastly, cancer-associated osteoblast and hydroxyapatite were able to promote tumor growth and metastasis in vivo. To conclude, bone marrow derived MSCs are circulating stem cells that participate in the establishment of the pathogenic stroma in breast cancer. Owing to their multipotency, MSCs give rise to cancer-associated osteoblasts that induce pro-malignant mineralization in situ. Subsequently, cancer cells harbor increased intracellular calcium concentration, enhanced proliferation and metastasis. We foresee the development of new stroma-targeted therapies that prevent the mineralization of tumor tissue and reduce metastasis in breast cancer patients.

EPFL2014

Elucidating the role of lymphatic vessels within the tumor microenvironment of breast cancer

Ingrid Maria van Mier

Breast cancer is the most common cancer in women worldwide, with an estimated 1.7 million newly diagnosed cases in 2012. Despite the many clinical manifestations, metastatic disease is the main cause of death, and is responsible for 90% of all breast cancer-related deaths. Aggressive carcinomas of the breast preferentially spread via the lymphogenous route, and often co-opt and actively remodel the lymphatic vasculature in order to invade and metastasize to their draining lymph nodes (LNs) and, ultimately, to distant organs. Indeed, expression of vascular endothelial growth factor (VEGF)-C, the principal lymphangiogenic growth factor, by the tumor or recruited ancillary cells has been shown to correlate both with LN and distant metastasis, and shorter overall survival (OS), and LN status represents an important prognostic factor for patients diagnosed with breast cancer. Although traditionally considered as passive conduits that solely mediate tumor cell escape, more recent research aimed at discerning the interactions between the developing tumor and its associated lymphatic vessels has revealed that the lymphatic vasculature actively promotes lymphogenous metastasis of invasive tumor cells. Likewise, collaborative interactions between tumor cells and a multitude of other tissue-resident and recruited ancillary cells, which together constitute the tumor microenvironment, not only coercively contribute to tumor growth, progression and metastasis, but also suggest that interactions among primed stromal cells themselves may be important in the process of metastatic dissemination as well. Notably, expansion of tumor-associated lymphatic vessels in the tumor periphery leads to increased lymphatic drainage from the tumor to the tumor-draining LN, and interstitial flow-induced mechanical changes may alter tensional homeostasis within the tumor through stimulation of local fibroblasts that remodel and stiffen the extracellular matrix (ECM). Furthermore, VEGF-C-induced remodeling of the tumor-associated lymphatic vasculature has been shown to directly suppress the anti-tumor immune response, thereby promoting tolerance to the nascent tumor. Thus, to explore whether tumor-associated lymphatic vessels promote tumor metastasis not only via interactions with the incipient tumor, but also through cross-talk with the surrounding stromal cells, the different components of the tumor microenvironment, specifically tensional homeostasis and anti-tumor immunity, were evaluated upon modulation of lymphatic vessel growth in various experimental models of breast cancer. Accordingly, inhibition of VEGFR-3-mediated signaling upon administration of an antagonistic antibody in a genetically engineered preclinical mouse model specifically reduced the number of lymphatic endothelial cells (LECs) in the tumor, whereas conversely, orthotopic inoculation of a stable murine breast cancer cell line with enhanced expression of VEGF-C induced an expansion of the lymphatic endothelium. Although either experimental approach affected either regional or distant metastatic dissemination of the primary tumor to LN or the lungs, respectively, these effects did not seem to be mediated by interactions of the tumor-associated lymphatic vasculature with the tumor microenvironment in these particular experimental models.

EPFL2017

Elucidating the role of lymphatic vessels within the tumor microenvironment of breast cancer

Ingrid Maria van Mier

EPFL2017

The role of recruited bone-marrow derived mesenchymal stem cells in the establishment of the tumor stroma and a growth-supportive environment

Jean-Paul Abbühl

EPFL2014

Investigation of migration of fibroblast cells on polyacrylamide hydrogels with a gradient in mechanical properties

The role of recruited bone-marrow derived mesenchymal stem cells in the establishment of the tumor stroma and a growth-supportive environment

Elucidating the role of lymphatic vessels within the tumor microenvironment of breast cancer

Investigation of migration of fibroblast cells on polyacrylamide hydrogels with a gradient in mechanical properties

Elucidating the role of lymphatic vessels within the tumor microenvironment of breast cancer

The role of recruited bone-marrow derived mesenchymal stem cells in the establishment of the tumor stroma and a growth-supportive environment