Abstract P3-03-17: Can polyploid tumor cells possessing stem cell features be induced in resistant breast carcinomas?

Abstract

Abstract Cancer stem cells are believed to be responsible for radio- and chemoresistance of malignant tumors. In vitro studies demonstrate that ionizing radiation is capable of reprogramming cancer cells from non-stem state into stem state [1, 2]. Moreover, the embryonic stemness cassette was found to be expressed in tumor cells (including breast cancer cells) after they were polyploidized as a result of genotoxic stress [2, 3], thus prompting us to suppose that the polyploid cells and their descendants released by depolyploidization can possess stem cell characteristics. The aim of the current work is to test whether polyploid cells having stem cell features can be also induced in vivo, namely in locally advanced breast carcinomas as a result of neoadjuvant chemotherapy (NAC), assuming that this process is not autonomous, but rather stipulated by the tumor microenvironment. The study population consisted of 30 breast cancer patients of age ranged from 31 to 75 y. o. diagnosed in the Latvian Oncology Center of the Riga East University Hospital between 2013 and 2015. The tissue specimens were collected after the patients' informed consent was obtained in accordance with the Ethics regulations. The clinico-pathologic information about these patients, including Ki-67 index and the status of ER, PR and HER2 receptors, was obtained from the aforementioned clinics. The majority of patients (n = 28) had locally advanced breast cancer, predominantly Stage III disease. Both diagnostic biopsy and operation material, such as primary tumors surgically removed after NAC using standard doses of paclitaxel and doxorubicin, were subjected to DNA content analysis with image cytometry. Ploidy-related parameters, such as DNA index and the percentage of cells exceeding 4.5c (presumably proliferating and polyploid cells), were determined. Immunofluorescence staining was applied to evaluate expression of such markers/factors as proliferation (Ki-67), stemness (SOX2 and NANOG) and invasiveness (CD44). At the time of diagnosis, 14 patients had primary tumors possessing near-triploid clones, and these cases in comparison with 16 other cases comprised of near-euploid clones had 4.5-fold increase of percentages of cells exceeding the ploidy of 4.5c (p < 0.05) and 1.3-fold increase of percentages of cells positive for Ki-67 (p > 0.05). Of 10 cases diagnosed as “triple-negative”, 6 were near-triploid. Among those cases that showed the resistance to NAC (grades 1 and 2 by Miller-Payne histopathologic scoring), 67% were near-triploid. Polyploidization, which in some resistant cases is gained by NAC, was likely to be attributed to near-triploid clones. Notably, polyploid cells were positive for Ki-67, SOX2, NANOG, and CD44. Thus, these non-quiescent polyploid cells can possess the invasiveness and self-renewal features that were also seen in descendants after depolyploidization. Perhaps, reversible polyploidy plays a definite role in gaining the resistance of tumor cells to chemo- and radiotherapy in vivo. 1. Ghisolfi L. et al. PLoS ONE 2012; 7: e43628. 2. Lagadec C. et al. Stem Cells 2012; 30: 833-44. 3. Salmina K. et al. Exp Cell Res 2010; 316: 2099-112. Citation Format: Gerashchenko BI, Salmina K, Eglitis J, Erenpreisa J. Can polyploid tumor cells possessing stem cell features be induced in resistant breast carcinomas? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-17.