Prostate Tumor Cells' Overexpression of Notch, Hedgehog Associated with Docetaxel Resistance and Metastasis

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(ChemotherapyAdvisor) – Development of docetaxel resistance in hormone-refractory prostate cancer (HRPC) is likely driven by subpopulations of stem-like cells that exhibit upregulated Notch and Hedgehog signaling, according to a preclinical study published in Cancer Cell.

The research team identified “a population of prostate cancer cells, existing both in cell lines and patient samples, which exhibits resistance to docetaxel, an undifferentiated phenotype, dependence on combined Notch and Hedgehog signaling, and high tumor-initiating capacity,” reported lead author Josep Domingo-Domenech, MD, PhD, Assistant Professor of Pathology at Mount Sinai School of Medicine in New York, and colleagues.

The docetaxel-resistant cells establish a molecular link between drug resistance and tumor progression, the authors noted.

“This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways,” Dr. Domingo-Domenech and coauthors reported. “These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis.”

Some of the cells were identified in all clinical HRPC biopsy samples analyzed, but subpopulations were significantly larger in metastatic tumors. In 31 primary tumors, they represented a mean 1.3% (±0.94%) of HRPC cell populations, compared to 3.2% (±2.2%) in metastatic tumors (P<0.0001).

The findings might lead to the development of “new diagnostic and prognostic tests, as well as new treatment strategies, the authors reported.

Targeting Notch and Hedgehog signaling inhibited AKT and Bcl-2 expression and depleted the population of docetaxel-resistant cells, they reported – “suggesting a therapeutic strategy for abrogating docetaxel resistance in HRPC.”


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