circulating-tumor-cell-lines-an-innovative-tool-for-fundamental

Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research

Metastasis is a leading cause of cancer death. Despite improvements in treatment strategies, metastatic cancer has a poor prognosis. We thus face an ...

Montpellier University

Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH(high) cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH(high) CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618-28. ©2016 AACR.

Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.

Metastatic process is described as a "dissemination of neoplastic cells in a distant secondary site, in which cells proliferate to develop a mass of cells partially differentiated". The vast majority of death in solid cancers is the consequence of metastasis development which lead to vital organ dysfunction. In the present review, either recent discoveries or controversial subjects associated with metastasis process will be discussed. Indeed epithelia-mesenchymal transition (EMT), circulating tumor cells, tumor dormancy, colonization in distant organ and cancer stem cells are tackled.

[Not Available].

[Cancer stem cells in colon cancer].

[Cancer stem cells and metastatic dissemination].

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1/Prox1/LGR5 endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

Julie Pannequin

Department of Physiology and Cancer,
Institute for Functional Genomics,
Department of Physiology and Cancer, Institute for Functional Genomics

Montpellier University

Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research

Julie Pannequin

Department of Physiology and Cancer,Institute for Functional Genomics,Department of Physiology and Cancer, Institute for Functional Genomics

Montpellier University

Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research

Department of Physiology and Cancer,
Institute for Functional Genomics,
Department of Physiology and Cancer, Institute for Functional Genomics