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Cancer Stem Cell Research

Carla Boccaccio, M.D.
Associate Professor University of Torino Medical School
E-mail: carla.boccaccio@ircc.it
Phone. +39.011.9933208
Fax. +39.011.9933225

pub Publications

Research topic:

Cancer stem cells and resistance to standard and targeted therapies

Background:

Like normal tissues, tumors such as colorectal cancer or glioblastoma are structured according to a hierarchy that includes two main components. At the hierarchy’s apex there is a (small) subpopulation of ‘cancer stem cells’ (CSC) able to self-renew, namely to endlessly propagate, and support tumor histogenesis, regeneration, and dissemination. At the hierarchy’s base there is an (ample) subpopulation of cells that, unlike CSC, have limited self-propagation ability, and tend to aberrantly differentiate and die. This model implies that, to cure the tumor, CSC must be eradicated. This goal is challenging, as CSC are often inherently resistant to therapies that so far have proven effective against the hierarchical basis of tumor cells, therapies that also include the most innovative agents, targeted at the genetic alterations driving cancer pathogenesis. To improve therapeutic outcomes, it is mandatory to identify and attack the molecular and genetic mechanisms underlying CSC resistance to conventional chemo- and radio-therapy, or to agents targeted at molecular lesions.

Research achievements:

In CSC isolated from glioblastoma (GBM-CSC), we have shown that the wild-type MET oncogene (the HGF receptor) is a functional marker of a specific subset of CSC, it activates a signalling pathway that sustains the DNA damage response, and counteracts cell death induced by ionizing radiation. As result, MET inhibition sensitizes GBM-CSC to radiotherapy in vitro and in vivo, and promotes regression of tumors obtained by GBM-CSC transplantation through eradication of the radioresistant GBM-CSC subpopulation. In CSC isolated from metastatic colorectal cancer (CRC-CSC), we’ve shown that several growth factors, including HGF and members of the EGF family, counteract the proliferative blockade imposed by EGFR inhibitors, currently used to treat metastatic CRC with significant but incomplete success. In mouse models obtained by CRC-CSC transplantation, we’ve shown that the therapeutic efficacy of standard EGFR inhibition is greatly enhanced by concomitant inhibition of MET and multiple members of the EGFR family.

Conclusions and perspectives:

The MET oncogene and EGFR, are both essential to sustain CSC viability and long-term propagation in tumors such as GBM and CRC. In GBM, where MET and EGFR are often expressed in a mutually exclusive manner, we’ve provided preclinical evidence that MET targeting impairs CSC properties, and increases the effectiveness of current therapies aimed at affecting DNA integrity and cell survival (e.g. radiotherapy). In CRC, we dissected the relative contribution of the four members of EGFR family and MET to CSC propagation and tumorigenicity. These results can instruct clinical trials that associate MET or EGFR family inhibitors with standard therapeutic protocols. Current work is aimed at identifing (i) the genetic and molecular context that modulates the CSC response to MET and EGFR inhibitors; (ii) the intratumoral CSC genetic and phenotypic heterogeneity, which must be recognized to refine the targeted treatment of each individual tumor.

 staff Staff

Elena Casanova, MSc
Phone: 011 993.3229
Email: elena.casanova@ircc.it

Francesca Orzan, PhD
Phone: 011 993.3229
Email: francesca.orzan@ircc.it

Marta Prelli, MSc
Phone: 011 993.3229
Email: marta.prelli@ircc.it

Gigliola Reato, MSc
Phone: 011 993.3229
Email: gigliola.reato@ircc.it

Federica Verginelli, PhD
Phone: 011 993.3229
Email: federica.verginelli@ircc.it

About

The Candiolo Cancer Institute is a private non-profit institution founded and supported by the Fondazione Piemontese per la Ricerca sul Cancro-Onlus (FPRC) and operated by the Fondazione del Piemonte per l’Oncologia (FPO: co-founded by FPRC and the Regione Piemonte).