More findings from TFRI’s prestigious hypoxia team are continuing to change the cancer research landscape when it comes to understanding the role of the mTOR signalling pathway in the development and aggressiveness of prostate cancer.
The group’s latest study, led by Dr. Brad Wouters (Princess Margaret Cancer Centre, University Health Network, Toronto) and published in Molecular Cancer Research (February 2018), highlights two key findings. The first is that the mTOR targets 4E-BP1 and 4E-BP2 proteins play a tumour suppressive function even in the context of constitutive PI3K activation driven by PTEN loss in prostate cancer. Their deletion accelerates tumorigenesis, or the production of tumours. The mTOR signalling pathway is a central regulator of protein synthesis and cellular metabolism that responds to the amount of energy, nutrients, oxygen, and growth factors available. The new study demonstrates it retains aspects of this role even in the case of its deregulation.
The second key finding is that these same two proteins, and the mTOR pathway, play a key role in the survival of hypoxic cells in these tumours. Patients respond poorly to treatment if their tumours are low in oxygen (hypoxic), and these tumours are more likely to grow and spread aggressively. The ability to restrain mTOR signalling during hypoxia, even in the context of upstream PI3K activation driven by PTEN loss, is essential for the survival of hypoxic cells. Thus, despite the more rapid tumour development in mice lacking these genes, the tumours that develop have lower levels of hypoxia.
The findings of the present study shed light on key upstream pathways that regulate hypoxia tolerance and thus the establishment of aggressive tumours in prostate cancer. Targeting the pathways that regulate mTOR activation, which is a common strategy in many cancers, may thus influence the formation of therapy resistant and aggressive hypoxic cells.
Prostate cancer is the most common type of cancer affecting Canadian men, and is the third leading cause of death amongst this demographic.
Study: The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer
Authors: Mei Ding, Theodorus H. Van der Kwast, Ravi N. Vellanki, Warren D. Foltz, Trevor D. McKee, Nahum Sonenberg, Pier P. Pandolfi, Marianne Koritzinsky, and Bradly G.Wouters.
Funding: This study was partially funded by a long-term grant from The Terry Fox Research Institute.