Membrane-type matrix metalloproteinases in pericellular proteolysis and melanoma cell invasion
Year: 2013
Type: dissertation
Abstract: Tumor microenvironment comprised of extracellular matrix (ECM) and non-malignant cells has profound effects on cancer progression. Membrane-type matrix metalloproteinases (MT-MMPs) are involved in the modulation of tumor microenvironment. MT1-MMP is a prototype of MT-MMP family, which is overexpressed in many types of cancer, where it promotes tumor cell invasion through collagen-rich tissues. The biological functions of another member of the MT-MMP family, MT3-MMP, have remained largely unknown. MT3-MMP is expressed in the adult brain, as well as brain tumors and nodular melanoma. The purpose of this thesis was to elucidate the functions of MT1-MMP and MT3-MMP in melanoma cell invasion. To understand the pericellular growth regulation, we searched for endogenous enzymes which could release latent TGF-β from endothelial cell extracellular matrix. Neovessel formation is a prerequisite for tumor growth. Pericellular modulation of the ECM by MT1-MMP releases matrix-associated growth factors and bioactive peptides, which further affect angiogenesis and tumor cell biology. We found that MT1-MMP modulated subendothelial extracellular matrix, and cleaved latent TGF-β binding protein-1 (LTPB-1), with subsequent release of latent TGF-β complexes from the ECM. Thus, MT1-MMP-mediated LTBP-1 cleavage provides a mechanism for the tightly controlled release of matrix-associated TGF-β at the sites of neovessel formation. To elucidate the functions of MT-MMPs in melanoma cell invasion, we analyzed the expression of MT1-MMP and MT3-MMP from biopsies of normal human skin, benign nevi, and melanoma metastases. MT3-MMP was upregulated in lymph node metastases of human melanoma, while MT1-MMP expression was comparable in all biopsies. By culturing melanoma cells in 3D collagen and fibrin matrices, we found that MT3-MMP was associated with expansive melanoma growth in 3D collagen, but promoted their sprouting growth in 3D fibrin. In in vivo xenograft experiments, MT3-MMP expressing melanoma xenografts grew slowly, while MT3-MMP silencing enhanced tumor growth rate by over twofold. Interestingly, high MT3-MMP expression in murine xenografts and a human melanoma tumor was associated with prominent lymphatic vessel invasion but negligible blood vessel invasion of melanoma cells. Silencing of MT3-MMP reduced lymphatic invasion but facilitated blood vessel invasion of melanoma cells over ~10-fold. MT3-MMP reduced cell surface MT1-MMP in vitro and in vivo, resulting in limited collagen invasion in vitro and collagen accumulation in vivo. This suggested that low collagenolytic ability of MT3-MMP-expressing melanoma cells resulted in decreased blood vascular invasion. These cells invaded instead into more permissive lymphatic vessels. Since lymphatic vessel invasion is associated with metastatic spread in melanoma, MT3-MMP expression may serve as a new prognostic factor in this disease.
Source: Työväentutkimus Vuosikirja
Author: Olga Tatti
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2110652212