Androgen-sensitive Prostate Cancer Survival And Progression Is Supported By Neuroendocrine Prostate Cancer Cells

Dr. Christopher Evans, University of California, Davis School of Medicine presented data showing that androgen insensitive prostate cancer cells can secrete neuropeptides that support the growth and migration of androgen sensitive prostate cancer cells in the castrate environment.

Neuroendocrine (NE) cells are present in all developing and adult normal prostates. The researchers hypothesized that NE cells are androgen independent (AI) and secrete neuropeptides that support androgen sensitive cell proliferation in the absence of androgens. In this study, GRP overexpressing LNCaP cells (LNCaP-GRP) were developed through transfection and selection. Xenograft tumors grown in nude mice with the LNCaP-GRP cells were re-cultured and termed GRP Pro cells. Soft agar growth under androgen-depleted conditions was performed to illustrate in vitro chimeric AI growth of both AI and coexistent LNCaP cells. Scratch migration assay was performed to demonstrate chemotactic migration in both AI and AS cells. Castrated SCID mice were orthotopically co-implanted with GRP-Pro and LNCaP cells tagged with red and green fluorescent proteins, respectively. Frozen sections of the tumors were viewed under fluorescence microscopy for color appearance and distribution.

GRP-Pro cells grew aggressively in soft agar assay by forming more than 100 fold more colonies than the control LNCaP cells. When the LNCaP cells were co-plated with GRP-Pro cells, the colony formation of the former increased by more than 10 fold, suggesting paracrine support from the GRP-Pro cells. Migratory activity of LNCaP cells was enhanced 2-fold when plated with GRP-Pro cells. Tumors harvested from SCID mice co-implanted with the two cell lines showed both green and red fluorescence, compared to no tumor growth in mice implanted with only green LNCaP cells. Growth, migration and soft-agar colony formation were all inhibited using the src-kinase inhibitor, AZD0530.

This data demonstrates that neuropeptide expressing LNCaP cells are AI and can support the AI survival and growth of parental cells in a paracrine fashion. This effect is mediated through src-kinase and can be inhibited with a novel src-kinase inhibitor.

By Christopher P. Evans, M.D.

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