Prostate cancer (PCa) epithelial cells have a critically important interaction with the surrounding tumor stromal microenvironment, and this feedback relationship stimulates PCa progression and metastasis. PCa stroma is composed of activated myofibroblasts that produce growth, angiogenesis, migration factors, and extracellular matrix, all of which contribute to tumor invasiveness. Disrupting this mutual-dependency tumor stromal-epithelial interaction leads to marked inhibition of tumor growth and blocks metastasis. Investigators in the Kraft laboratory at the Medical University of South Carolina have discovered that the PIM1 serine-threonine protein, known to be elevated in prostate cancer, is significantly increased in human prostate stromal cells and plays an important role in controlling fiibroblast cell biology. Increasing the level of PIM1 kinase in a normal prostate fibroblast cell line leads t the transdifferentiation of these normal cells to activated myofibroblasts, followed by the increase in the PDGF receptor and secretion of multiple factors that play a critical role in stimulating tumor growth. Further, these PIM activated myofibroblasts are capable of markedly stimulating the growth and migration of human prostate epithelial cells. These exciting results lead to the unique hypothesis that activated PIM1 kinase plays an important role in transdifferentiation of prostate fibroblast cells potentially controlling prostate cancer growth an migration. This hypothesis suggests that small molecule PIM inhibitory compounds in phase I trials and available to the Kraft laboratory have the potential to interrupt this epithelial:stroma feedback relationship and block the growth of these tumors.
The specific aims will evaluate this hypothesis by: 1) determining whether increases in PIM1 in freshly isolated cancer associated fibroblasts drive and section of growth and migration factors and whether this can be inhibited by drugs which block the PIM kinase; and 2) examining whether PIM1 overexpressing prostate myofibroblasts are capable of induced epithelial cell malignancy and tumor growth in animal models. The proposed study design will make use of a novel glycoprotein labelling procedure that employs click chemistry to measure the stromal secretome, and a subrenal capsular recombination assay in mice. These studies will employ novel small molecule PIM inhibitors developed by AstraZeneca and Genentech that are entering the clinic for cancer therapy. These studies will markedly increase the understanding of the role of PIM1 in prostate cancer fibroblast activity and develop the rationale for using PIM inhibitors as a potential method of interrupting stromal:epithelial interaction inhibiting prostate tumor growth.
Prostate cancer is the second most common cause of cancer death in men in the U.S. Growth and metastasis of prostate tumors, which directly impacts the mortality rates, are driven by interactions between certain cell types that make up this cancer. This application, under Dr. Andrew Kraft's direction, will develop an understanding of the feedback relationship between these varied cell types, which will provide the rationale for developing newer therapeutic approaches.
| Zemskova, Marina Y; Song, Jin H; Cen, Bo et al. (2015) Regulation of prostate stromal fibroblasts by the PIM1 protein kinase. Cell Signal 27:135-46 |
