Scientists have identified a subtype of cancer stem cell (CSC) that appears to be linked with acquired resistance to chemotherapy and may represent a tumor’s therapeutic Achilles’ heel. A Columbia University-led team used in vitro and in vivo models of prostate cancer to identify a subpopulation of cancer cells that survive docetaxel therapy. These cells lacked differentiation markers and HLA class I antigens, but overexpressed Notch and Hedgehog signaling pathways, and demonstrated potent tumor-initiating capacity.
Notably, in vitro studies showed that treating these CSCs using either short hairpin RNAs (shRNAs) to knock down genes critical for Notch and Hedgehog signaling rendered them sensitive to docetaxel therapy. And when mice bearing human prostate tumors were treated using chemical inhibitors of Notch and Hedgehog signaling as well as docetaxel, they demonstrated remarkably reduced tumor growth compared with control mice.
The researchers subsequently identified a small subpopulation of cells with this docetaxel-resistant phenotype in all primary and metastatic clinical prostate cancers evaluated, and found that the cell population was much higher in metastatic patients treated using docetaxel than in untreated patients. In fact the abundance of this cell population in human patients was linked with tumor aggressiveness and poor prognosis. “Thus, the Docetaxel-resistance phenotype was consistently identified in prostate cancer as a small subpopulation, which is associated with both Docetaxel resistance and canonical prognostic parameters,” state Carlos Cordon-Cardo, M.D., et al in their published paper in Cancer Cell.
“The researchers claim their work represents the first time that CSCs of the prostate have been identified as the basis for drug resistance and tumor progression. “By targeting these newly identified CSCs we are attacking the foundation fo tumor growth, rather than treating the symptoms of it,” adds lead author Josep Domingo-Domenech, M.D. “The novel discovery of this cell population could lead to the development of new tests for early cancer diagnosis, prognostic tests, and innovative therapeutic strategies.”
The Columbia University team, together with colleagues at the Memorial Sloan-Kettering Cancer Center and Mount Sinai School of Medicine, report their findings in a paper titled “Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch and Hedgehog-Dependent Tumor-Initiating Cells.”