Blanc, V.M.; (2008) Expression, regulation and roles of semaphorins and their receptors in prostate and prostate cancer. Doctoral thesis , University of London.

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Abstract

Prostate cancer (PCa) has become a major public health issue it is the second most common cause of cancer-related death in the UK. PCa preferentially metastasises to the bone. Semaphorins are an important family of membrane bound or secreted signalling proteins, which control cell movement (or chemotaxis). They have a role in the nervous, immune and vascular systems, but have not previously been studied in prostate. To determine if semaphorins and their receptors are expressed In normal and pathological prostate, profiling experiments were performed by (q)RT-PCR in prostate cell lines and tissues. Results show that semaphorins and receptors are ubiquitously expressed, suggesting autocrine and paracrine regulation of semaphorin signalling in prostate particularly an autocrine signalling of Semaphorin3A in bone metastasis derived cells. Results also show that expression of secreted semaphorins is regulated by hypoxia which strongly downregulates semaphorin 3e in primary tumour derived cells, whereas semaphorin 3c is strongly upregulated. Particular focus was brought on semaphorin 3e, whose expression is strongly increased in epithelial cells derived from benign prostate hyperplasia, non-neoplastic tissue, and bone metastasis derived cells. A Semaphorin3E expression construct was made and the protein produced in mammalian cells to study its effects on cell morphology and adhesion by immunocytochemistry and adhesion assays. Results show that Semaphorin3E inhibits integrin-mediated cell adhesion while it initiates vinculin-mediated focal adhesion formation, which suggest that Semaphorin3E may play important regulatory roles in prostate cancer metastasis. The effects on cell movement of frequent missense mutations of PlexinBl receptor, associated with prostate primary tumours and metastases, was studied by migration assays. Results show that the three mutations of PlexinBl increase cell migration in absence of ligand Semaphorin4D, and further increase migration in its presence. Together these results suggest that semaphorin signalling has a key role in prostate cancer progression.

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