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Official websites use. Share sensitive information only on official, secure websites. Understanding molecular mechanisms of tumorigenesis and identifying factors that regulate stem cell self-renewal are important avenues of cancer research. Stoyanova et al. These results suggest that blocking Trop2 activation represents a possible therapeutic strategy in epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear.
In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain.
The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.
Trop2 is a type I transmembrane glycoprotein highly expressed in various epithelial cancers, such as advanced squamous cell carcinoma of the oral cavity and colorectal, pancreatic, gastric, and ovarian cancer, and its high levels correlate with poor prognosis and survival Nakashima et al. Monoclonal antibodies targeting Trop2 exhibit potent anti-cancer activity through cytotoxicity in multiple xenograft models of cancer, including prostate, pancreatic, breast, colon, endometrial, and lung cancer Young et al.
Knockdown of Trop2 abrogates the growth of colon cancer cell lines and inhibits tumor initiation and progression in mice Wang et al. Recently, Trop2 was demonstrated to play dual functions in tumorigenesisβas a tumor suppressor and an oncogene Wang et al. Cancer cells share multiple characteristics with adult tissue stem cells, such as self-renewal and proliferative capacity.