BackgroundCirculating epithelial tumor cell (CETC) analysis is a promising diagnostic field for estimating the risk for metastatic relapse and progression in patients with malignant disease. CETCs characterization can be used as a liquid biopsy for prognostic and predictive purposes in breast and other cancers. IGF-IR and VEGFR-2 play an important role in tumor growth and the progression of cancer disease. The purpose of the current study was therefore to investigate their expression on CETCs.MethodsCETCs were determined from the blood of 50 patients suffering from breast cancer. The number of vital CETCs and the expression of IGF-IR and VEGFR-2 were investigated using the maintrac® method.ResultsIGF-IR and VEGFR-2 expression on the surface of CETCs were detected in 84% of patients. A statistically high correlation was found between IGF-IR and VEGFR-2 (r = 0.745 and p<0.001) on the CETCs. The co-expression of both receptors was confirmed in some experiments and ranged between 70% and 100%. Statistically significant correlations were observed between the number of CETCs and IGF-IR (r = 0.315 and p<0.05) and VEGFR-2 (r = 0.310 and p<0.05) expression. The presence of CETCs and the level of IGF-IR and VEGFR-2 expression were not associated with tumor stage, hormone receptor status or nodal/distant metastasis.SummaryIn this study, a parallel and co-expression of IGF-IR and VEGFR-2 was examined on the surface of CETCs in breast cancer patients for the first time. Characterization of CETCs may be a promising approach for the rational design of targeted anticancer therapies.
Background: The detection of tumor cells circulating in the peripheral blood of patients with breast cancer is a sign that cells have been able to leave the primary tumor and survive in the circulation. However, in order to form metastases they require additional properties such as the ability to adhere, self renew and grow. Here we present data that a variable fraction among the circulating tumor cells detected by the maintrac® approach express mRNA of the stem cell gene nanog and of the adhesion molecule vimentin and are capable of forming tumor spheres a property ascribed to TIC. Patients and methods: Between 10 to 50 circulating epithelial antigen positive cells detected by the maintrac® approach were selected randomly from each of 20 patients with breast cancer before and after surgery and isolated using automated capillary aspiration and deposited individually onto slides for expression profiling. In addition, the circulating tumor cells were cultured without isolation among the white blood cells from 5 patients with breast cancer in different stages of disease using culture methods favoring growth of epithelial cells. Results: Although no EpCAM mRNA positive cells expressing stem cell genes or the adhesion molecule vimentin were detected before surgery, 10 to 20% of the cells were found to be positive for mRNA of these genes after surgery. Most surprisingly, it was possible to grow tumor spheres (Fig 1) from these circulating cells without previous isolation in all patients in a fraction comprising between 1% of the epithelial antigen positive cells in patients with newly diagnosed tumor up to 10% in a patient with advanced breast cancer. Conclusion: We here show, that among the peripherally circulating tumor cells a variable fraction is able to express stem cell and adhesion properties and can be grown into tumor spheres, a property ascribed to cells capable of initiating tumors and metastases. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-13.
32 Background: Even after the complete resection of a malignant tumor the menace remains, that cells that have dissociated from the tumor might resettle in distant organs and grow into life-threatening metastases. Therefore we have developed an approach (maintrac) to detect and monitor the circulating tumor suspect epithelial cells in blood. However, the question arises whether these cells have the potential to grow into metastases. Methods: Using a nondissipative approach with only one enrichment step of red blood cell lysis, the cells from the pellet, containing the white blood cells together with the putative tumor cells were cultured under conditions favoring the growth of epithelial cells. At 7, 14 and 21 days the cultured cells were stained with anti-EpCAM antibody and inspected for the appearance of epithelial antigen positive spheroids. Results: Peripherally circulating cells from patients with malignant tumors in different stages of disease were analyzed for the presence of circulating epithelial tumor suspect cells and the frequencies of tumorspheres. Tumorspheres could so far be grown from 79% of 36 patients in whom more than 1700/ml epithelial tumor suspect cells were detected. Numbers of tumorspheres varied from 1 to 29 /ml and correlated with the aggressiveness of the tumor. Surprsingly the numbers were highest in patients who had not yet received any systemic therapy after surgery. The size of the spheres increased from day 7 to day 21. The spheres were negative for CD24 and positive for CD44. They highly expressed ALDH1 and thus exhibited typical features of stem cells. Conclusions: Here, we demonstrate that the tumor suspect cells, detected in our approach contain a subpopulation with stem cell-like properties capable of growing into tumorspheres. The frequency and growth potential of cells capable of forming spheres seems to be dependent from the properties of the primary tumor. The possibility to grow tumorspheres from peripherally circulating tumor cells may open up a new field, where the relevant cells with stem cell properties from individual patients can now be specifically analysed further for genetic endowment, transcriptional activity, heterogeneity and stem cell markers.
Background: Among the cells that are disseminated from a malignant tumor only very few are capable to resettle in distant organs and grow into life-threatening metastases. Therefore, the question arises how and whether such cells which have the potential to grow into metastases can be detected. It has been shown that a subpopulation of cells from breast cancer tissue can form so-called mammospheres with stem cell features. Here we show that such tumor spheres can also be grown from peripherally circulating tumor cells from breast cancer patients in different stages of disease Materials and Methods: Using a nondissipative approach with only one enrichment step of red blood cell lysis, the cells from the pellet, containing the white blood cells together with the putative tumor cells were cultured under conditions favoring the growth of epithelial cells. At 7, 14 and 21days the cell cultures were inspected for the appearance of spheroids staining with anti-EpCAM, anti-CD24 and anti-CD44 antibody and.expressing ALDH1. Results: Peripherally circulating cells from patients with malignant tumors in different stages of disease were analyzed for the presence of circulating epithelial tumor suspect cells and the frequencies of tumorspheres. Tumorspheres could so far be grown from 79% of 36 patients in whom more than 1700/ml epithelial tumor suspect cells were detected. Numbers of tumorspheres varied from 1 to 29 /ml and correlated with the aggressiveness of the tumor. Surprsingly the numbers were highest in patients after surgery who had not yet received any systemic therapy. The size of the spheres increased from day 7 to day 21. The spheres were negative for CD24 and positive for CD44. They highly express ALDH1 and thus exhibite typical features of stem cells. Conclusion: Here, we demonstrate that the circulating tumor cells, detected in our approach contain a subpopulation with stem cell-like properties capable of growing into tumorspheres. The frequency and growth potential of cells capable of forming spheres seems to be dependent from the properties of the primary tumor. The possibility to grow tumorspheres from peripherally circulating tumor cells may open up a new field, where the relevant cells with stem cell properties from individual patients can now be specifically analysed further for genetic endowment, transcriptional activity, heterogeneity and stem cell markers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-1.
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