Abstract
The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1(-/-) mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(α)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1(-/-) mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2. In these tumors, PTEN expression was lower. Emilin1(-/-) mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors were also increased in Emilin1(-/-) mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype.
Highlights
The microenvironment in which a tumor originates plays a critical role in tumor development and progression [1]
By different in vivo models, we showed that EMILIN1 exerts a suppressive role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes
Tumor development in Emilin1À/À mice subjected to a skin carcinogenesis protocol was accelerated, and the number and size of skin tumors was significantly increased compared with their WT littermates
Summary
The microenvironment in which a tumor originates plays a critical role in tumor development and progression [1]. It consists of cells, mainly fibroblasts, immune and vascular cells, soluble molecules, and extracellular matrix (ECM) constituents that coevolve during tumorigenesis generating a complex cross-talk for both positive and negative influences on tumor cells [2]. Authors' Affiliations: 1Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano (PN), Italy; 2Department of Biomedical Science and Technology, and 3MATI (Microgravity, Ageing, Training, Immobility) Excellence Center, University of Udine, Udine, Italy. Danussi: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA
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