Study Identifies Signaling Pathway Responsible for Generating Slowly Proliferating, Chemoresistant Cancer Cells
Although scientists know that all cancers contain a mixture of both rapidly and slowly proliferating cancer cells, which complicates the detection and treatment of patients with cancer and may cause disease relapse long after apparently curative treatment, the circumstances and molecular details of how slow proliferators are produced has not been well understood. Now, scientists investigating how dividing cancer cells sometimes produce daughter cells with different AKT protein kinase levels, leading one daughter cell to proliferate at a slower pace than the other, have identified the process by which signaling molecules regulate cell proliferation.
The study findings by Dey-Guha et al may provide a better understanding of cancer biology and insight in the development and use of clinical inhibitors that target these molecules. The study is published in Molecular Cancer Research.
Study Methodology and Findings
The scientists used various molecular biology techniques, including immunofluorescence staining, collagen matrix studies, confocal imaging, and Western blotting and immunoprecipitation, on colon and breast cancer cell cultures to investigate how dividing cancer cells spawn slow-proliferating cells. They found that decreased signaling through beta1-integrin, a molecule found on the surface of most cancer cells, reduced activity of the FAK signaling molecule, activated the mTORC2 complex, and suppressed AKT1 protein levels through TTC3/proteasome-mediated degradation.
“Interestingly, any dividing cancer cell appears capable of triggering the beta1-integrin pathway that we describe to produce AKT1 slow proliferators,” wrote the researchers. “This facultative behavior presumably occurs if dividing cancer cells encounter irregularities in extracellular type I collagen, although additional cooperative factors yet to be discovered may also be required. Moreover, we find that activation of beta1-integrin signaling with monoclonal antibodies or inhibition of mTORC2 signaling with small molecules reduces asymmetric cancer cell division and the production of these slow proliferators. Our findings might, therefore, suggest potentially new avenues for experimentally or therapeutically manipulating and studying the production of AKT1 slow proliferators both in vitro and in vivo.”
“Prior to these studies, we thought that asymmetric suppression of AKT might just relate to random fluctuations in protein levels during cell division,” Sridhar Ramaswamy, MD, Associate Professor of Medicine at Massachusetts General Hospital Cancer Center and Harvard Medical School and corresponding author of the study, said in a statement. “We discovered that this is not the case. It is actually regulated by a potentially targetable signaling pathway, which may offer new avenues for reducing the proliferative heterogeneity within tumors for therapeutic effect.”
Dr. Ramawamy is the corresponding author of the study.
Funding for the study was provided by Stand Up to Cancer, the National Cancer Institute, the Howard Hughes Medical Institute, Susan G. Komen, the Prostate Cancer Foundation, DNPq, and Instituto de Salud Carlos III Postdoctoral Fellowship Award.
The study authors reported no conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
