Abstract
We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.
Highlights
Metastasis is a multistep process in which cancer cells invade the surrounding tissue at the primary tumor site, enter the vascular system, and extravasate and grow in other organs
We found that the expression of Sema3E correlates with the ability to form lung metastasis in four murine adenocarcinoma cell models each consisting of paired metastatic and nonmetastatic cell lines from the same breast tumors [10]
We have investigated the relevance of SEMA3E to human disease by examining human cancer cell lines and solid tumors from cancer patients
Summary
Metastasis is a multistep process in which cancer cells invade the surrounding tissue at the primary tumor site, enter the vascular system, and extravasate and grow in other organs. In an attempt to identify genes involved in lung metastasis of breast cancer cells, we have previously compared gene expression profiles of metastatic and nonmetastatic subpopulations derived from murine mammary adenocarcinomas. Semaphorins belong to a diverse group of genes that encode growth guidance cues (the others include the ephrin, netrin, and slit genes). These cues cooperate with growth factors to achieve the proper development of the nervous and cardiovascular systems [11,12,13]. SEMA3F acts as a direct chemorepellent for endothelial cells and when overexpressed in melanoma cells, SEMA3F induces a poorly vascularized, nonmetastatic tumor type [23]
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