To identify genes uniquely associated to metastatic spreading, a comparative global gene expression analysis of different metastatic cells was performed. Comparison of KM12 and HCT116 colon cancer models, HC11 transformed mammary cells and the BSp73-AS rat pancreatic carcinoma revealed that TROP2 was the only gene up-regulated across different metastatic models, tumor types and animal species. A large-scale analysis of human tumors (1755 cases) revealed expression of Trop-2 in most cancers and a dramatic up-regulation in metastases from colon, stomach, breast and ovary tumors. To assess if Trop-2 may play a causal role in metastatic spreading, TROP2-transfected KM12SM colon cancer cells were orthotopically injected in nude mice. TROP2-overexpressing transfectants demonstrated increased metastatic potential to the liver. Deletion of the HIKE domain of Trop-2 severely diminished, whereas that of the whole cytoplasmic region vastly increased metastatic diffusion, indicating the existence of both metastatic enhancing and silencing regions in the Trop-2 cytoplasmic tail. These findings also raised the possibility of a direct stimulatory role of Trop-2 in cancer cell growth. TROP2 siRNA indeed inhibited and overexpression potently stimulated the in vitro growth of tumor cells. Trop-2-positive transformed cells generated aggressively growing tumors in nude mice. A deletion of the cytoplasmic region of Trop-2 abolished this stimulatory capacity, as did the removal of the S303 PKC phosphorylation site. Proteomic and phosphoproteomic analysis showed that multiple PKC isoforms partecipate to the Trop-2 signaling network. Dominant negative PKCs and PKC siRNAs selectively abolished the Trop-2- caused growth stimulation. These findings demonstrate that Trop-2 is a novel, widespread, stimulator of human cancer growth. They also identify Trop-2 as a unique marker and causal factor of metastatic cancer, and candidate it for novel diagnostic and therapeutic procedures.

Comparative global gene expression analysis identifies TROP2 as a major determinant of growth and metastatic spreading of human cancer

Saverio Alberti
Conceptualization
;
2007-01-01

Abstract

To identify genes uniquely associated to metastatic spreading, a comparative global gene expression analysis of different metastatic cells was performed. Comparison of KM12 and HCT116 colon cancer models, HC11 transformed mammary cells and the BSp73-AS rat pancreatic carcinoma revealed that TROP2 was the only gene up-regulated across different metastatic models, tumor types and animal species. A large-scale analysis of human tumors (1755 cases) revealed expression of Trop-2 in most cancers and a dramatic up-regulation in metastases from colon, stomach, breast and ovary tumors. To assess if Trop-2 may play a causal role in metastatic spreading, TROP2-transfected KM12SM colon cancer cells were orthotopically injected in nude mice. TROP2-overexpressing transfectants demonstrated increased metastatic potential to the liver. Deletion of the HIKE domain of Trop-2 severely diminished, whereas that of the whole cytoplasmic region vastly increased metastatic diffusion, indicating the existence of both metastatic enhancing and silencing regions in the Trop-2 cytoplasmic tail. These findings also raised the possibility of a direct stimulatory role of Trop-2 in cancer cell growth. TROP2 siRNA indeed inhibited and overexpression potently stimulated the in vitro growth of tumor cells. Trop-2-positive transformed cells generated aggressively growing tumors in nude mice. A deletion of the cytoplasmic region of Trop-2 abolished this stimulatory capacity, as did the removal of the S303 PKC phosphorylation site. Proteomic and phosphoproteomic analysis showed that multiple PKC isoforms partecipate to the Trop-2 signaling network. Dominant negative PKCs and PKC siRNAs selectively abolished the Trop-2- caused growth stimulation. These findings demonstrate that Trop-2 is a novel, widespread, stimulator of human cancer growth. They also identify Trop-2 as a unique marker and causal factor of metastatic cancer, and candidate it for novel diagnostic and therapeutic procedures.
2007
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3162587
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