Panc02-mTrop2 cells proliferated 2

Panc02-mTrop2 cells proliferated 2.7 times faster than Panc02-GFP cells at day 5. adenocarcinoma cells overexpressing human Trop2. Conclusions These findings demonstrate some of the pathogenic effects mediated by mTrop2 expression on cancer cells and the importance of targeting this cell surface glycoprotein. This study also provides the first indication of a molecular signaling pathway activated by Trop2 which has important implications for cancer cell growth and survival. Background Trop2 is a cell surface glycoprotein belonging to the em TACSTD /em gene family and highly overexpressed by a variety of epithelial carcinomas with low to restricted expression in normal tissues [1-6]. Clinical data has shown a positive correlation between Trop2 expression levels and tumor aggressiveness and metastasis, and a negative correlation with overall patient survival [1-6]. Trop2 is highly conserved among species with a 79% identical amino acid composition between KIAA1819 human and murine Trop2. This protein was initially found to be highly expressed in trophoblast cells, which arise from epithelial trophectoderm cells and become invasive, phagocytosing and displacing uterine epithelial cells. This allows for the penetration of the uterine stroma in order to establish vascular interactions with the maternal blood supply [7,8]. Trop2 expression has also been observed in murine and human prostate basal cells with stem cell characteristics [9]. Basal stem progenitor cells with high Trop2 expression were shown to give rise to basal, luminal and even neuroendocrine cells em in vivo /em . A similar behavior has also been reported in hepatic oval cells which are considered facultative hepatic stem cells and shown to express Trop2 [10]. It thus appears that Trop2 provides crucial signals for cells with a requirement for proliferation, survival and invasion such as trophoblast cells or cells with progenitor-like characteristics. These same characteristics might be conferred to cancer cells by overexpression of this surface YL-109 glycoprotein. Trop2 has recently been identified as an oncogene leading to the invasiveness and tumorigenesis of colon cancer cells, but the underlying signaling mechanisms activated by this protein YL-109 are still YL-109 unknown [11]. It has been shown YL-109 that cross-linking this protein with antibodies results in a significant rise in intracellular calcium [Ca2+] from internal stores which could have a significant effect on the activation and progression of the cell cycle as well as activation of other signaling pathways [12-15]. The cytoplasmic tail of Trop2 appears to play an important role in signaling. One study has shown the presence of a phosphatidylinositol 4,5-bis phosphate (PIP2)-binding sequence highly homologous to that of gelsolin [16]. Within this sequence there is a conserved serine residue which is phosphorylated by protein kinase C (PKC) [17]. Thus, PKC and mitogen-activated protein kinases (MAPKs) including ERK1/2 may be involved in Trop2 induced tumor cell growth [17,18]. The purpose of this study was to determine the effects of murine Trop2 expression (mTrop2) in cancer cells and to start delineating the pathways activated by this molecule. We found that mTrop2 expression resulted in increased cell proliferation at low serum concentrations with an increased percentage of cells entering S phase. Expression of mTrop2 also led to increased cell migration, foci formation and anchorage independent growth and translated to increased tumor growth in both subcutaneous and orthotopic tumor models. mTrop2 expression also led to increased liver metastasis as well as increased levels of phosphorylated p42/p44MAPK (ERK1/ERK2) which is a master regulator of the G1- to S-phase transition [18,19]. This translated to a rise in cyclin D1 and cyclin E protein levels with a downregulation of p27. This study provides new evidence that Trop2 contributes YL-109 to tumor pathogenesis at least in part by activating the ERK1/2 MAPK pathway which has important implications for a variety of cellular pathways as it.