BBB Seminar: Agnès Noël
Contribution of cancer associated fibroblasts and lymphatic endothelial cells in the remodelling of a collagen-rich tumor microenvironment
Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Cancer), University of Liège, Belgium
Carcinoma growth and metastatic dissemination are dependent on the formation of a permissive tumor stroma composed of extracellular matrix (ECM) and a heterogeneous population of activated stromal cells, including fibroblasts (cancer-associated fibroblasts or CAFs, myofibroblasts), endothelial cells, immune cells, and bone marrow (BM)-derived stem and progenitor cells. These tumor supporting stromal cells communicate with cancer cells through both paracrine and juxtacrine signals mediated by ECM component deposition, remodeling enzyme production, and growth factor or cytokine/chemokine secretion. The interactions occurring between tumor cells and host cells support the formation of new blood vessel (angiogenesis) and lymphatic vessels (lymphangiogenesis) involved in metastatic dissemination. These host cells contribute to ECM turnover by secreting a number of ECM-degrading proteases such as the matrix metalloproteinases (MMPs). Among MMPs, the collagenase subfamily contributes to matrix remodeling by their ability to degrade fibrillar collagens. This subfamily includes the fibroblast interstitial collagenase (MMP1), neutrophil collagenase or collagenase 2 (MMP8), and collagenase 3 (MMP13). In addition, MMP14 (MT1-MMP) and gelatinases (MMP2 and MMP9) display collagenolytic activities.
We have recently addressed which fibroblast subset produces interstitial collagenases in the tumor microenvironment. CAFs consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. We have demonstrated the contribution of BM-derived cells to generate specific fibroblast subsets that produce MMP13 and affect cancer cell invasion. Our data support the concept of fibroblast subset specialization with BM-derived alpha-smooth muscle actin (α-SMA)-positive cells being the main source of MMP13, a stromal mediator of cancer cell invasion. Next, we have explored how lymphatic endothelial cells deal with interstitial collagen. This step is rate limiting for the formation of new lymphatic vessels that facilitate metastasis into lymph nodes. We will discuss the mechanisms used by lymphatic endothelial cells to deal with the collagen barrier to form new lymphatics. Our recent findings are shedding light on the key contribution of MMP2 during the complex process of lymphangiogenesis.
Host: Donald Gullberg, Department of Biomedicine