Scott Cramer Lab

The current focus of my research is on the molecular dissection of signaling pathways in prostatic cells with a focus on vitamin D, the identification of prostate cancer tumor initiating or stem cells, identification of a novel prostate tumor suppressor at 6q15 and understanding epithelial-stromal interactions in normal and abnormal ductal morphogenesis of the prostate.

Vitamin D Synergism
I have a long-standing interest in vitamin D signaling and agents that might potentiate or stimulate vitamin D signaling.  We have several published studies on the synergism inhibition of prostate cancer growth by vitamin D and the soy isoflavanoid genistein.  We have a funded R01 in this area and currently a clinical trail is underway based on our preclinical studies.  We have identified several candidate signaling molecules that are being evaluated for their role in vitamin D and genistein signaling both in vitro and in in vivo preclinical models.

Prostate Cancer Tumor Initiating (Stem) Cells
We have developed techniques to isolate and characterize prostate stem/progenitor cells from adult mice (Barclay et al, in press).  Using this system we have identified pathways that may be critically involved in stem cell self-renewal and differentiation and that are disrupted in prostate cancer cells.  We are testing the roles of these pathways in self-renewal a differentiation of prostate progenitor/stem cells.  In a separate project on cancer stem cells we have initiated a collaboration with Rafael Davalos in Bioengineering at Virginia Tech.  He has a high throughput method of differential cell isolation based on electrophoretic properties.  We are testing if we can isolate prostate cancer tumor initiating cells based on their electrophoretic properties alone or in combination with cell surface markers.

The Tumor Microenvironment
The development of normal and abnormal glandular structures in the prostate is controlled at the endocrine and paracrine levels by reciprocal interactions between epithelium and stroma.  To study these processes we have developed an efficient method of fresh human prostate tissue acquisition for reproducible isolation of cells from defined histologies.  Using this system we have demonstrated fundamental differences in the inductive capabilities of stromal cells derived from normal or diseased prostatic tissue.  Normal stromal cells have no apparent ability to induce epithelial cell growth in a prostate recombination model.  Stromal cells derived from benign prostatic hyperplasia induce sharply circumscribed structures.  Histological examination of these grafts reveals densely packed, well-organized tubular epithelium with minimal stroma, sharply demarcated from surrounding renal tissue. Stunningly, recombinants with cancer associated stromal cells produce much more robust growth than the other recombinants tested.  Histological assessment of the grafts reveals moderately differentiated, highly vascularized tumors with invasion into surrounding renal tissue.  The results support a growing body of work from a number of different epithelial tumor systems demonstrating that the tumor microenvironment, and specifically, epithelial-mesenchymal interactions are critically important for tumorigenesis.  These studies argue that more focused attention should be directed towards the nature of cancer associated stroma.  On hypothesis we are exploring is that there are functional interactions with stromal-derived factors and mutations in the epithelium.