Prostate cancer is the second most common cancer and the second leading cause of cancer death in American men. Now researchers have discovered key molecular players that cause prostate cancer to progress into a very aggressive form of the disease called neuroendocrine prostate cancer that currently has no effective treatment. The discovery opens new avenues to explore for therapeutics to treat neuroendocrine prostate cancer.
“We have found novel pathways that promote neuroendocrine prostate cancer,” says lead author Lucia R. Laguino, PhD, professor in the Department of Cancer Pharmacology, Physiology and Biology and director of the PhD program in Genetics, Genomics and cancer biology at Thomas Jefferson University. She and her team published the new research online November 7, 2022 in the journal Scientific reports.
Most prostate cancers are a type of disease called prostate adenocarcinoma. Other types of prostate cancer, including neuroendocrine tumors, are rare. However, unlike prostate adenocarcinoma, neuroendocrine prostate cancer is very aggressive and can quickly spread to other parts of the body. Effective treatments for prostate adenocarcinomas do not work for neuroendocrine prostate cancers.
Prostate cancers caused by adenocarcinoma can progress to neuroendocrine cancer of the prostate. Until now, how this transition occurs has been a mystery.
To better understand how neuroendocrine prostate cancer develops, Dr. Languino and his colleagues searched for biomarkers of the disease. In previous work, they found that a molecule known as the aVb3 integrin is abundant in mice and humans with neuroendocrine prostate cancer, but absent in prostate adenocarcinoma.
To search for molecules unique to neuroendocrine prostate cancer, researchers found that expression of the aVb3 integrin in prostate cancer cells increased expression of a known neuroendocrine prostate cancer marker and significantly increased expression of a molecule called the Nogo receptor 2 (NgR2).
The finding “was a big breakthrough,” said Dr. Languino, who is also a researcher at the Sidney Kimmel Cancer Center – Jefferson Health. Indeed, NgR2 is a protein present in nerve cells, where it contributes to neuronal functions. It has never been studied before in any cancer.
Dr. Laguino and her colleagues wanted to know what this molecule, a neuronal protein, does in cancer.
A first experiment revealed that NgR2 binds to the aVb3 integrin. The scientists also found that in mice with prostate neuroendocrine tumors, both aVb3 integrin and NgR2 were present in the primary tumor and in cancerous lesions that had formed in the animals’ lungs. A follow-up experiment clearly showed that the integrin aVb3 and NgR2 are required for neuroendocrine prostate cancers.
When Dr. Laguino and his team reduced the amount of NgR2 in neuroendocrine prostate cancer cells, neuroendocrine markers also decreased. The results suggest that NgR2 plays a role in the development of neuroendocrine prostate cancer. Lowering the amount of NgR2 also reduced the ability of cancer cells to grow and move, indicating that NgR2 may have a role in spreading cancer to other parts of the body, in a process known as metastasis name. Metastasis is often what makes cancers deadly.
“These two molecules, integrin aVb3 and NgR2, seem to create a lethal combination,” says Dr. Laguino.
She and her colleagues are now looking for a molecule or antibody that would block the effect of NgR2, or the aVb3/NgR2 integrin complex, to inhibit their ability to promote the growth and development of neuroendocrine prostate cancer, and make cancer more responsive to therapy.
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