Identification of the required hallmarks for the tumor cells to disseminate to the liver represents an important milestone to delay cancer progression, and consequently to avoid the harmful consequences for patients. Largely unknown, a myriad of cell properties seem to cooperate in a successful metastatic process and in the chemo-/radio- therapeutic resistance. Our aim is to define the intrinsic characteristics of tumor cells that may contribute to epithelial-mesenchymal transition (EMT) in early and late metastatic events. We previously observed that: i) metastatic cells reaching the liver microenvironment display cancer stem features associated with EMT and increased TGFβ1-signaling (Zubeldia et al. Proceedings AACR, 2010; 51, #2304); ii) hepatic secondary tumors are enriched with a subpopulation of cells with a distinctive Sca1+ phenotype and a concurrent increased expression of other cancer stem markers (Zubeldia et al. Proceedings MRS-AACR, 2010; #A105). First, we demonstrated the high tumorigenicity of these metastatic liver-derived cell lines after subcutaneous injection in nude mice, without obvious correlation with their origin regarding TGFβ1-signaling. However, as shown by bioluminescent imaging, some of the novel metastatic liver-derived cell sublines were unable to achieve metastases following intrasplenic injection in C57BL/6J mice. We also noted a differential efficiency of each clone in primary tumor formation in this experimental model. Importantly, we found that co-injection of these cells (isolated from liver metastases) with non transformed hepatocytes (AML12) resulted in a significant increase of metastasis formation. We show an important role of normal cells for metastatic spread in early steps of tumor formation, and suggest the protective activity that the untransformed epithelial cells may have throughout the metastatic progression. We will present the therapeutic implications of our findings for the clinical treatment of carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3358. doi:10.1158/1538-7445.AM2011-3358
The liver is a major target organ for metastasis. Development of metastases requires an early release of tumour-initiating-cells from the primary tumour and adhesion of metastatic-cells into a permissive niche. We hypothesized that Epithelial-Mesenchymal Transition (EMT) underlies not only the early events, but also the promotion of the most advanced stages of a successful dissemination process to the liver. It is believed that TGFβ1 might allow tumour-initiating-cells to acquire cancer stem cell properties via EMT as a mechanism that modulates the microenvironment contributing to primary and also metastatic tumor progression. However, the mechanism of EMT induction by TGFβ1 and its involvement in liver metastases remain largely unknown. Aiming to recapitulate the hepatic metastases, we established a murine model of highly metastatic colon carcinoma cells in the context of TGFβ1-signaling. To this end, luciferase-expressing cells (MC-38luc) were pre-treated with TGFβ1 (100 pM, 48 h), before intrasplenic injection of 106 cells in C57BL/6J mice. Larger primary tumours were consistently observed and liver metastasis was achieved more rapidly after injection of MC-38luc+TGFβ1 cells, than after injection of untreated MC-38luc cells. Histological examination of liver micrometastasis also revealed slightly increased staining of Ki67, α-SMA and F4/80 markers in MC-38luc+TGFβ1 tumours. Splenic co-injection of these liver-metastatic-stem cells with non transformed hepatocytes (AML-12 cells) accelerated the incidence of liver metastasis, indicating the supportive role of the normal hepatic parenchyma. Intraperitoneal injection with a novel TGFβ1-inhibitory peptide P17 (obtained from a peptide library binding to TGFβ1) resulted in reduced liver metastasis and decrease of both CECs and CEPs. We isolated liver-metastatic cells that showed higher cellular proliferation as compared to the parental counterparts. These cells posses increased tumorogenicity in vivo, a complete lack of E-cadherin expression, and increased TGFβ1/EMT signalling properties that all relate to stem cell features. Our results provide an insight into the molecular events leading to TGFβ1-mediated malignant progression and indicate that targeting TGFβ1/EMT might represent an optimal therapeutic strategy by impairing tumor growth, stemness and further liver metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2304.
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