Interaction between tumour and microenvironment - molecular mechanisms of cell migration in canine tumours

Abstract

Different steps forward have been made in the recent years to identify the molecular determinants in carcinogenesis and the evidence of a multistep process where cancer cells accumulate multiple and consecutive genetic alterations has been formulated. Recently, tumour progression has been recognized as the product of a complex crosstalk between tumour cells and their surrounding and supporting tissue, named tumour stroma. This stroma is known to influence the growth of cancer and it is composed by several types of cells, including endothelial cells of blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells, such as macrophages, mast cells, neutrophils, lymphocytes and mesenchymal stem cells. The supportive microenvironment is generate and modulated by cancer cells through the production and activation of stroma growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). Concomitant with altered growth-factor expressions, induced by their autocrine and paracrine effect on the tumour and stromal cells, cancer cells are able to produce proteolytic enzymes, such as Matrix metalloproteinases (MMPs), which operate the remodelling of extracellular matrix (ECM) and basement membrane, thus activating cell-surface and ECM-bound growth factors. All these processes are described to contribute to the extensive crosstalk between the microenvironment and the cancer cells. Therefore, the microenvironment is implicated in the regulation of cell growth, determining angiogenesis, tumour invasion and metastasis, and impacting the outcome. Even if stromal cells are not malignant, their role in supporting cancer growth is vital to the survival of the tumour. For this purpose, cells of microenvironment have become an attractive target for therapeutic agents. The present project has been divided in different tasks to identify the molecular mechanisms implicated in cell migration, angiogenesis and tumour growth led by stroma cells and their crosstalk with cancer cells in different neoplasia in dog. Canine mammary tumour, cutaneous mast cell tumour, lymphoid leukaemia and lymphoma were selected for the study and gene expression profiling and proteomic analysis of different growth factors (VEGF-TGF-beta-PDGF) and MMPs were analyzed in association with their possible prognostic and predictive role and crosstalk. Several important results have obtained highlighting the background of the tumour progression and the role of microenvironment in veterinary oncology. Selected results are shown below: - MMP-2, MT1-MMP, MMP-9 were significantly involved in canine mammary tumour and a significant role of the stromal compartment was described; - MMP-9 and VEGF-A were associated with the histological tumour grade in cutaneous mast cell tumour; - MMP-9, MT1-MMP, TIMP-1 and VEGF were correlated in T-cell lymphoma and in dogs with higher stage; - A potential role of MT1-MMP and TIMP-2 in the pathogenesis of canine acute lymphoblastic leukaemia has been discovered; - In chronic lymphocytic leukaemia, residual normal leukocytes have shown a significative influence in the expression of MMP-9, MT1-MMP, VEGF and TIMPs; - Lymphoma and leukaemia in vitro model exhibited a significative discrepancy that enhanced the importance of microenvironment in vivo; - PDGF-B mRNA expression was identified in canine T-cell lymphoma and cutaneous lymphomas. A functional autocrine and/or paracrine loop of growth stimulation was proposed due to the co-expression of PDGFs and PDGFRs at different time point during disease. Therefore, the obtained results may significantly improve the understanding of cancerogenesis of the most frequent tumours in dogs. The summarized data here show a primary role for the microenvironment during carcinogenesis. Development of novel cancer therapies that target the process of metastasis formation, tumour growth and differentiation, by interfering with the ability of cancer cells to transmigrate into blood and lymph vessels and to invade the connective tissue, is widely expected in veterinary oncology. Further data are necessary to indicate that the use of chemopreventive agents to control the function and behaviour of cells in the microenvironment might be an important approach to the overall control of cancer