Abstract
Prostate cancer (PCa) is the most common noncutaneous cancer in men worldwide. One of its major treatments is androgen deprivation therapy, but PCa frequently relapses as aggressive castration resistant local tumors and distal metastases. Hence, the development of novel agents or treatment modalities for advanced PCa is crucial. Many tumors, including PCa, first metastasize to regional lymph nodes via lymphatic vessels. Recent findings demonstrate that the bioactive lipid lysophosphatidic acid (LPA) promotes PCa progression by regulating vascular endothelial growth factor-C (VEGF-C), a critical mediator of tumor lymphangiogenesis and lymphatic metastasis. Many of the underlying molecular mechanisms of the LPA–VEGF-C axis have been described, revealing potential biomarkers and therapeutic targets that may aid in the diagnosis and treatment of advanced PCa. Herein, we review the literature that illustrates a functional role for LPA signaling in PCa progression. These discoveries may be especially applicable to anti-lymphangiogenic strategies for the prevention and therapy of metastatic PCa.
Highlights
Prostate cancer (PCa) is one of the most common cancers in aging men
Since the VEGF tyrosine kinase receptors (VEGFRs) axis has been designed and extensively tested clinically to reduce angiogenesis in advanced PCa and all the clinical trials to date have been unsuccessful, this discussion has provided new perspectives on the challenges involved in targeting lymphangiogenesis/lymphatic metastasis and vascular endothelial growth factor-C (VEGF-C) signaling via lysophosphatidic acid (LPA) signaling in PCa
The expression profiles of LPA receptors are diverse among PCa cell lines, with more malignant cell lines exhibiting LPA receptor-mediated effects in PCa progression
Summary
Prostate cancer (PCa) is one of the most common cancers in aging men. According to the statistics based on 2011–2015 cases from the National Cancer Institute, USA, the number of new cases of PCa was 112.6 per 100,000 men per year, and the number of deaths was 19.5 per 100,000 men per year during this period. LPA has been shown to enhance the growth and metastasis of several cancers by increasing vascular endothelial growth factor-A and -C (VEGF-A and VEGF-C) expression and secretion, which stimulates angiogenesis and lymphangiogenesis [16,17,18]. These effects of LPA on VEGF-A and VEGF-C have been observed in PCa cells, where VEGF-C (but not VEGF-D) was found to be especially important in mediating lymphangiogenesis and tumor metastasis in advanced. We review the molecular regulation of LPA-mediated lymphangiogenesis in PCa
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