RELAZIONE ATTIVITA’ SCIENTIFICA PREMIO “GENDER INNVATION”
Dott.ssa Federica Finetti
(Università di Siena)
Relazione relativa al progetto di ricerca vincitore del premio SIF-Takeda in farmacologia oncologica “Epidermal growth factor and prostaglandin E2 in tumor progression”
Background
Chronic inflammation is a critical component of tumor progression. Several inflammatory diseases increase risk of cancer. Moreover, the activation of a pathway that promotes the production of inflammatory cytokines and the recruitment of inflammatory cells is observed in tumors that are not directly related to inflammatory condition (1).
We and others have previously reported that exogenous PGE2 contributes to tumor progression either by activating signaling cascades downstream to specific prostaglandin E receptors (EPs) or transactivating signaling pathways downstream to epidermal growth factor receptor (EGFR). In squamous cell carcinoma, we demonstrated that PGE2 promotes tumor cell growth and invasion by activation of EP2 type receptor, cSrc and protein kinase A, which, in turn, transactivates EGFR and its downstream signaling (2). Inhibition of EGFR activation, through monoclonal antibodies (as cetuximab) or small tyrosine kinase inhibitors (i.e. erlotinib and gefitinib), is an important treatment modality in several tumors, where EGFR receptor is highly expressed, constitutively activated or mutated. However, not all patients respond to this therapy. Potential mechanisms for lack of response to EGFR inhibition include constitutive activation of signaling pathways independent from EGFR (3-5). Since the resistance to EGFR inhibition may be circumvented by combination therapy employing EGFR inhibitors together with treatment targeting downstream EGFR signals, the identification of new molecular target is fundamental.
The hypothesis at the basis of this project is that in tumor cells PGE2 and EGFR cooperate to increase tumor malignance. To explore this idea we decide to study prostate cancer, where overexpression of EGFR promotes metastatic progression and correlates with high Gleason score, and where EGFR inhibition has been unsatisfactory for the lack of response to target therapy.
Results
By using the DU145 cell line, a model of EGFR dependent metastatic castration-resistant prostate cancer, expressing or silenced for mPGES-1, we investigated the involvement of mPGES-1/EGFR signaling cascade on tumor growth and EMT phenotype. We also evaluated the mPGES-1 contribution to tumor cell responsiveness to the EGFR inhibitors.
We investigated whether blocking the EGFR activation, either with the monoclonal antibody, cetuximab, or the tyrosine kinase inhibitor, erlotinib, would affect tumor growth. By comparing prostate cancer cells bearing an intact mPGES-1 functional enzyme (SC) with those in which the mPGES-1 was silenced (KD) we found a marked change in cell phenotype. The presence of mPGES-1 in SC cells resulted in a massive PGE2 output and a marked increase of EGFR expression relative to KD cells. SC showed mesenchymal traits in their gene pattern, in the expression of vimentin and fibronectin and in their invasiveness capability. Further, overexpression of mPGES-1 also correlated with increased in vivo tumor growth. Erlotinib treatment reduced the growth of both SC and KD xenograft tumors, but the tumor mass where significantly smaller when PGE2 was inhibited, suggesting that it could be of advantage to combine EGFR and PGE2 signaling inhibition, in prostate cancer cells.
Reference List
(1) Mantovani A. Cancer: Inflaming metastasis. Nature 2009 1;457(7225):36-7.
(2) Donnini S, Finetti F, Solito R, Terzuoli E, Sacchetti A, Morbidelli L, et al. EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. FASEB J 2007 ;21(10):2418-30.
(3) Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009 18;101(4):715-21.
(4) Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 2009 1;27(16):2622-9.
(5) Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol 2009 1;27(7):1130-6.