Nearly 200 thousand men are diagnosed with prostate cancer every year. Most of the deaths associated with prostate cancer occur in advanced stages of the disease, which are the result of metastasis – the spreading of the tumor away from its origin.
Notch signaling pathway is involved in prostate cancer and, in a paper published June 2016 in The Journal of Clinical Investigation, researchers at Baylor College of Medicine and other institutions showed that, in a mouse model of the disease, Notch alterations promote metastasis.
In normal tissues of many species, Notch signaling pathway is crucial for tissue development and homeostasis, helping to maintain a balance of the body’s normal functions. Scientists studying the Notch pathway have reached a consensus that Notch signaling is altered during prostate carcinogenesis, but its role in prostate cancer remains inadequately defined.
“Most previous studies on the role that Notch plays in prostate cancer were performed in cultured cells in the laboratory. These studies produced contradictory results. Some studies concluded that Notch was an oncogene, that it promoted cancer development, and others that it was a tumor suppressor gene,” said Dr. Li Xin, associate professor of molecular and cellular biology at Baylor. “To gain a better understanding of Notch in prostate cancer we decided to study its role in an animal model in a defined genetic context.”
Xin and colleagues developed the mouse animal model according to previous analysis of human prostate cancer specimens that had revealed that Pten is a tumor suppressor gene whose loss-of-function correlates with prostate cancer progression. In addition, “we found an inverse correlation between the level of expression of Pten and the level of Notch activity,” said Xin. To reproduce the observations in human tissues, the researchers used a mouse model of prostate cancer with prostate specific loss-of-function of Pten to determine the role of Notch signaling in prostate cancer progression.
In this mouse model, the scientists discovered that activation of Notch signaling can drive tumor metastasis to major internal organs such as lung and liver. To determine how Notch drives metastasis, the scientists carried out further molecular studies.
“Our major conclusion is that Notch is able to increase the production of another molecule called FoxC2, which is very important for the metastatic potential of cells. If we suppress FoxC2, we can attenuate Notch-mediated metastatic activity,” said Xin.
“This mouse study showed directly in vivo that increased Notch activity can drive prostate cancer metastasis,” said Xin. “Future studies will aim to address whether Notch inhibition can suppress tumor metastasis. These studies will serve as solid rationale for treating human prostate cancer with Notch inhibitors.”
Other contributors of this work include Oh-Joon Kwon, Li Zhang, Jianghua Wang, Qingtai Su, Qin Feng, Xiang H.F. Zhang, Sendurai A. Mani, Robia Paulter, Chad J. Creighton and Michael M. Ittmann of Baylor College of Medicine and The University of Texas MD Anderson Cancer Center, Houston.
This project was supported by the National Institutes of Health (grants P30-AI036211, P30-CA125123, S10-RR024574, NIH R01-CA190378, R21-CA196570, U01-CA141497 and P30-CA125123) and the Cancer Center Shared Resources Grant.