Michael Freeman, PhD
David E. Retik Director
of Basic Urologic Research
|Academic Title||Professor of Surgery|
300 Longwood Avenue
Boston MA 02115
Dr. Freeman's research group focuses on studies directed toward understanding the molecular basis of genitourinary tract pathology of several kinds. The group primarily studies diseases involving the bladder, prostate and kidney. They have a long history investigating the function and regulatory features of the ErbB receptor tyrosine kinase ligand, heparin-binding EGF-like growth factor (HB-EGF), in a variety of contexts. In the lower urinary tract, their observations suggest that HB-EGF participates in "hypertrophic changes," such as tissue expansion, thickening, and degeneration, in the bladder's muscle layers. These phenomena are associated with debilitating and painful syndromes in children and adults, such as urinary tract obstruction, interstitial cystitis and benign prostatic hyperplasia. They are now studying the intracellular signaling systems that regulate bladder and ureteral smooth muscle cell growth using in vitro and in vivo approaches. In addition to its role as a regulator of muscle growth, HB-EGF is a prostate cancer cell mitogen and survival factor synthesized by interstitial smooth muscle cells of the human prostate stroma. This location and other recently acquired data suggest that HB-EGF is one of the long-hypothesized stromal mediators of prostate epithelial cell function.
Another area of interest involves the study of the mechanisms of signal processing through specialized cell membrane domains, called lipid rafts, in prostate cancer and urinary tract smooth muscle cells. The Freeman laboratory recently identified membrane cholesterol as an important regulator of the PI3K/Akt/mTOR signaling pathway, a signal transduction mechanism that is thought to be functionally involved in regulation of tissue size and in human prostate cancer progression. Their findings suggest a new explanation for the epidemiological link between prostate cancer and a diet rich in animal products or fat. Model systems currently in use in the lab to study this membrane microdomain include in vitro and ex vivo systems, mouse-human tumor xenografts and zebrafish.
A third area involves the study of the function of the calcium entry channel, CaT1/TRPV6, in epithelial cell physiology and malignant growth. In recent reports, Dr. Freeman and colleagues have described the first link between this selective ion channel and human prostate cancer and other malignancies, and have provided evidence that CaT1 is the major portal of calcium entry in the gastrointestinal tract epithelium.
- Zhuang, L., Kim, J., Adam, R.M., Solomon, K.R., and Freeman, M.R.? (2005) Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. Journal of Clinical Investigation 115:959-968.
- Cinar, B., De Benedetti, A., and and Freeman, M.R.? (2005) Post-transcriptional regulation of the androgen receptor by mammalian target of rapamycin. Cancer Research 65:2547-2553.
- Adam, R.M., Danciu, T., McClellan, D.L., Borer, J.G., Lin, J., Zurakowski, D., Weinstein, M.H., Rajjayabun, P., Mellon, J.K., and Freeman, M.R. (2003) A nuclear form of the heparin-binding EGF-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Research 63:484-490.