Tumour growth inhibition and anti‐metastatic activity of a mutated furin‐resistant Semaphorin 3E isoform

Abstract

Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.

Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis

“…These observations are reminiscent of the similar protumorigenic activity displayed by p61-sema3E, which is the FPPC cleavage product of sema3E that gains the ability to activate the ErbB2 receptor and thus promotes tumor progression. However, unlike p65-sema3C, p61-sema3E still retained the cytoskeleton collapsing activity of full-length sema3E (35,51). We have found preliminary evidence indicating that p65-Sema3C functions as a survival factor for A549 lung cancer cells, suggesting that the reported protumorigenic properties of sema3C may be due to p65-Sema3C.…”

The role of the semaphorins in cancer

“…[87][88][89][90] Since many types of tumor cells express semaphorin receptors it is not surprising that semaphorins have been found to inhibit the proliferation and metastatic spread of tumor cells by affecting tumor cells in a variety of ways. 71,[91][92][93] In addition some semaphorins have been found to inhibit tumor progression as a result of their effects on the tumor microenvironment. Processes such as the recruitment of various stromal cells such as macrophages to the tumor microenvironment can be affected by various semaphorins 94 but perhaps best studied are the effects of some semaphorins on tumor angiogenesis.…”

“…This logic led to the identification of several class-3 semaphorins such as sema3F as inhibitors of tumor angiogenesis and tumor progression and to their consideration as potential therapeutics for the treatment of cancer. 92,102,103 In contrast with the class-3 semaphorins, of which most have been characterized as anti-angiogenic and antitumorigenic factors, semaphorins such as sema4D, 104,105 sema5A, 106,107 sema6A, 108 sema4A 109 and sema7A 110 have been described as promoters of angiogenesis and as promoters of tumor progression. Such semaphorins are therefore considered as targets for the development of novel cancer therapeutics.…”

“…Interestingly, some semaphorins such as sema3C, sema6A and sema3E display dual activities and have been characterized in some publications as inducers of tumor progression 108,[111][112][113][114] and in other publications as inhibitors of tumor progression. 61,92,115,116 The mechanisms responsible for this duality are not yet completely clear and are likely the result of post translational processing and the formation of complex associations between semaphorin receptors and other types of membrane bound receptors such as various tyrosinekinase receptors and adhesion receptors.…”

“…Furthermore, this cleavage resistant point mutated sema3E inhibits the pro-metastatic activity of p61-Sema3E because it competes with p61-Sema3E for binding to plexin-D1. 92 However, in cases in which tumor cells do not express plexin-D1 or tyrosine-kinase receptors that associates with plexin-D1 it is possible that wild type sema3E which in the tumor microenvironment may contain a high proportion of p61-Sema3E, may also display anti-metastatic properties due to its anti-angiogenic effects. Over-expression of wild type sema3E which is susceptible to furin like proprotein convertases, nevertheless inhibited VEGF induced metastasis of melanoma cells, possibly due to inhibition of VEGF induced angiogenesis.…”