Nora M. Navone, M.D., Ph.D.
1981, 1989, University of Buenos Aires
The University of Texas M.D. Anderson Cancer Center
Department of Genitourinary Medical Oncology
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Nora M. Navone, M.D., Ph.D. 1981, 1989, University of Buenos Aires The University of Texas M.D. Anderson Cancer Center |
Research Interests:
In contrast with most other neoplasms, prostate cancer very specifically metastasizes to the bone, where it induces osteoblastic lesions. This suggests an interaction between prostate cancer cells and osteoblasts, which may impact on disease progression. In an in vitro model of prostate cancer bone metastases established in our laboratory, we showed that prostate cancer cells induce an increase in osteoblast growth and differentiation. Osteoblast differentiation was associated with upregulation of osteoblast specific transcription factor Cbfa1 and Osteocalcin, a downstream target of Cbfa1, as well as of other extracellular matrix proteins (procollagen type I and osteopontin). These findings suggest that prostate cancer cells promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent pathway. We are in the process of isolating the factor(s) that induce Cbfa2 expression.
Expression of two genes involved in cell proliferation and survival were found to be modulated in prostate cancer cells during co-culture with osteoblasts. Expression of insulin-like growth factor binding protein 3 (IGFBP-3) decreased, whereas MDM-2 expression increased. Lastly, we showed that expression of a molecule involved in bone resorption, osteoprotegerin (OPG) is decreased in osteoblasts co-cultured with prostate cancer cells. These data provide evidence that multiple molecular events affecting both bone formation and bone resorption concur to favor de novo bone formation by prostate cancer cells.
An osteoblastic reaction was also observed in vivo after intra-femoral injection of prostate cancer cells into SCID mice. This result is important because prostate cancer bone metastases are characteristically osteoblastic, and therefore our model system mimics the growth of prostate cancer cells within bone observed in the clinic. With the availability of appropriate in vitro and in vivo models of prostate cancer bone metastases we can now decipher the molecular events associated with prostate cancer growth within bone.
Clinical data suggested that p53 alterations may be important in the progression of prostate cancer and that wild-type p53 protein may play a role in some cellular responses to androgens. Our model system is an important tool for the study of the p53 and p21 signaling pathway in prostate cancer progression. Our laboratory is currently using this model in its efforts to study the role of p53 and p21 signaling pathways in the progression of prostate cancer to the androgen-independent, metastatic phenotype.
A tutorial could provide exposure to a variety of molecular and cellular techniques.
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