Fight Aging!

Most types of cancer are made dangerous by malignancy and metastasis, the ability to grow and spread rapidly. For many cancers these capabilities have been shown to be driven by a comparatively small population of cancer stem cells. One of the possibilities arising from the growing knowledge of stem cell biology is to turn off the stemness of cancer cells, reprogramming them to cease aggressive replication. As this paper indicates, however, efforts on this front are still in the very early stages of research:

Metastasis is the major factor responsible for the lethality of malignant breast cancer in human patients. Although various targeted and non-targeted therapies can occasionally control the progress of breast cancer, a significant portion of patients develop resistance to chemotherapy and experience metastatic recurrence. The epithelial to mesenchymal transition (EMT), a key developmental program in embryogenesis, has been found to be closely intertwined with the occurrence of metastasis in various human cancers. EMT can be prompted by the expression of multiple transcriptional factors and is controlled by several signaling pathways.

Towards the goal of understanding breast cancer metastasis, our group performed a cross-species expression profiling and identified Foxq1 as an EMT- and metastasis-promoting gene in breast cancer. Following this discovery, Foxq1 expression has been shown to promote EMT and metastasis in a wide array of human cancers. In line with the previously-mentioned link between EMT and stemness, we demonstrated that ectopic expression of FOXQ1 led to an increase in the stem-like phenotype. This increase in the stem cell population correlated with the induction of EMT. Mechanistically, we identified the receptor tyrosine kinases PDGFR α and β as downstream targets of FoxQ1.

Our study showed that knockdown of PDGFR α and β significantly decreased cell proliferation, migration and invasion. The effects were greatest when both α and β were knocked down. Knockdown of PDGFR α and β decreased lung metastases in vivo. These results strongly suggest that FoxQ1's role as a promoter of the cancer stem cell's phenotype is regulated in part by PDGFR activity. Our study demonstrates that EMT and stemness properties are not controlled by identical gene programs, at least in some cell lines. Inhibiting PDGFR α and β significantly reduced the stemness properties without impacting the mesenchymal-like phenotype of those cells. Since this inhibition correlated with a marked decrease in malignancy, our study suggests that the acquisition of stem-like properties may drive malignancy to a greater degree than EMT alone. Further studies must be done to identify other pharmacological targets that synergize with the stemness-promoting activity of PDGFRs. Reversing cancer stemness, together with conventional chemotherapy, could provide an ideal approach for prevent cancer recurrence and metastasis by eradicating both the bulk tumor cells and the cancer stem cells with self renewal capability.

Link: http://www.impactaging.com/papers/v7/n11/full/100846.html