In cancer treatment, anti-angiogenic therapies act against blood vessels, with eventual nutrient and oxygen deprivation [1]; indeed, cancer cells show high rates of glucose consumption, and rely on glycolysis instead of mitochondrial phosphorylation (the Warburg effect) [2]. In most cases anti-angiogenic drugs result in tumor growth arrest; however, at the end of treatment tumors often increase their invasiveness, likely due to selection induced by glucose deprivation and hypoxia [3]. Many data indicate that tumor growth is sustained by a celi subset termed Cancer Stem Cells (CSC) [4], able to form spheroids in vitro, and to generate tumors with high efficiency when injected into SCID animais; also, they resist toxic drugs thanks to expression of specific pumps. Thus, anti-VEGF refractoriness could be imputed to CSC resistance to nutrient deprivation. Little is known about CSC metabolism; indeed, elimination of this population may represent the very comerstone of anti-cancer therapy

Epithelial ovarian cancer (EOC) is the fifth most common cause of death from cancer in women. To date, the most commonly recognized markers for ovarian Cancer Stem Cells (CSC) are CD44 and CD117 (c-kit); CD44+/CD117+ ovarian cancer cells are able to form spheroids in vitro, to overexpress stem cell-associated genes, and to differentiate when transferred to serum-containing medium. In addition, these double-positive cells fit the operational definition of CSC, in that they generate tumors with high efficiency in SCID mice. However, little is known about CSC metabolic features; the idea pursued in this project, based on a solid body of preliminary data, is that anti-angiogenic treatment couid mostly select CSC via glucose deprivation. Thus, we will address the metabolic properties of CSC in EOC patients, to clarify whether ovarian CSC couid escape the Warburg effect, and identify key enzymatic pathways to be potentially exploited for therapeutic purposes

Aims

To characterize the phenotypic, genotypic and metabolic profile of cancer stem cells in ovarian cancer patientsto explore the effects of anti-angiogenic therapy on the frequency and features of cancer stem cells in ovarian cancer patientsbased on the above findings, to design locoregional interventions aimed at targeting cancer stem cells in ovarian cancer patients

5 Publications

Pastò A, Serafin V, Pilotto G, Lago C, Bellio C, Trusolino L, Bertotti A, Hohey T, Plateroti M, Esposito G, Pinazza M, Agostini M, Nitti D, *Amadori A, Indraccolo S: Notch3 signaling regulates Musashhi-1 expression in metastatic colorectal cells. Cancer Res. 74, 2106-18, 2014.

Pastò A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, Amadori A: Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 2014 Jun 30;5(12):4305-19155.

Grassi A, Di Camillo B, Ciccarese F, Agnusdei V, Zanovello P, Amadori A, Finesso L, Indraccolo S, Toffolo GM. Reconstruction of gene regulatory modules from RNA silencing of IFN-α modulators: experimental set-up and inference method. BMC Genomics. 2016 Mar 12;17:228. doi: 10.1186/s12864-016-2525-5.

Pagotto A, Pilotto G, Mazzoldi EL, Nicoletto MO, Frezzini S, Pastò A, Amadori A: Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis. 2017 Jul 20;8(7):e2943. doi: 10.1038/cddis.2017.327. PMID: 28726781

Mazzoldi EL, Pavan S, Pilotto G, Leone K, Pagotto A, Frezzini S, Nicoletto MO, Amadori A, Pastò A. A juxtacrine/paracrine loop between C-Kit and stem cell factor promotes cancer stem cell survival in epithelial ovarian cancer. Cell Death Dis. 2019 May 28;10(6):412. doi: 10.1038/s41419-019-1656-4.

Funding 

AIRC

People involved:
Paola Zanovello, Full Professor

Group members

Stefano Indraccolo, MD, IOV
Sonia Minuzzo, TA, University of Padova
Elena Mazzoldi, PhD, University of Padova
Ilaria Piga, PhD Student, University of Padova
Francesca Montenegro, PhD Student, University of Padova