The Role of CRIPTO Signaling in Lethal Prostate Cancer
Abstract
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-associated death in men. The survival rate of PCa patients is mostly determined by the extent of the tumor. If the cancer is confined to the prostatic gland, the median survival can be anticipated in excess of 5 years. Patients with locally advanced cancer are not usually curable and will eventually die of the tumor, although the median survival may be as long as 5 years. If PCa has spread to distant organs, current therapies are not curative, and the median survival drops to 1 to 3 years. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed, resulting in high expenses for the health system. Currently, PCa can be successfully treated surgically when still in its first phase of androgen dependency. Follow-up with androgen deprivation therapy will contain the cancer and reduce the possibility of metastasis. However, once the cancer becomes androgen-independent or “castration resistant,” therapy is no longer useful or successful. This particular population of patients that are castration-resistant is our targeted population. PCa arises from precursor lesions defined as prostatic intraepithelial neoplasia (PIN) or intra-ductal carcinoma (IDC) and progresses to a locally invasive disease and ultimately metastasis. PIN occurs in young men in their twenties, but clinically detectable PCa does not typically arise before the age of 60. Much effort has been put into characterizing every stage of human PCa and in deriving mouse models that mimic the human disease to aid in the development and preclinical testing of novel drugs. The castration-resistant stage, which is associated with the final and most aggressive stage of the cancer, is characterized by bone metastasis and has yet to be recapitulated in genetically engineered mouse models. Therefore, there is an urgent need to identify markers and therapeutic targets that specifically drive the castration-resistant stage of the disease associated with metastasis and poor patient prognosis. Cripto is a stem cell signaling protein that has been heavily implicated in human cancers. Cripto is a small protein that can be attached to the surface of cells or secreted into the extracellular space where it has activities that resemble those of other secreted growth factors. We previously demonstrated that Cripto binds to another protein called GRP78 on the cell surface and that this interaction is essential for Cripto signaling and regulation of stem cells and tumor cells. We have tested a candidate therapeutic agent called ALK4-Fc that blocks the ability of Cripto to bind GRP78 and thereby inhibits Cripto signaling. We have shown that Cripto is produced at high levels in the high Gleason human PCa, and we have also detected high levels of Cripto protein in bone metastases from human PCa patients. Our functional studies show that targeted reduction of Cripto levels inhibits growth and invasion of PCa cells grown in culture and, significantly, blocks bone metastases of these cells when they are injected into mice. Together, these findings suggest that Cripto signaling activity may cause stem cell behavior associated with the castration-resistant stage of the human disease and that blocking Cripto has therapeutic potential. In this application, we hypothesize that Cripto contributes to converting stem cells into cancer stem cells and that it sustains stem cell-like PCa cells linked to therapy resistance and metastasis. We postulate that Cripto blockade will have significant therapeutic potential in treating metastatic PCa, and its detection will improve patient stratification. To test these hypotheses, we will modulate Cripto signaling activity in prostate stem and cancer cells by manipulating the level genetically. We will determine the metabolic and transcriptomic landscape of the different cell population and determine whether C
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910432
Entities
People
- Marianna Kruithof-de Julio
Organizations
- United States Army
- University of Bern