Fontanella, Raffaela (2016) Innovative therapeutic tools to prevent BM-MSC recruitment and activity into tumor microenvironment. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Innovative therapeutic tools to prevent BM-MSC recruitment and activity into tumor microenvironment
Creators:
CreatorsEmail
Fontanella, Raffaelaraffaela.fontanella@alice.it
Date: 30 March 2016
Number of Pages: 98
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricoavvedim@unina.it
Tutor:
nomeemail
Zannetti, AntonellaUNSPECIFIED
Date: 30 March 2016
Number of Pages: 98
Uncontrolled Keywords: tumor microenvironment; mesenchymal stem cells; CXCR4; PDGFRβ
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Date Deposited: 13 Apr 2016 10:21
Last Modified: 05 May 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/10751

Abstract

Tumor progression is a multistep process in which cancer cells perform an intricate cross-talk with their surrounding stromal environment, generating a bidirectional communication that affects tumor survival, proliferation and aggressiveness. Among several cell types that constitute the tumor stroma, mesenchymal stem cells (MSCs) selectively migrate toward tumor microenvironment and contribute to the active formation of tumor-associated stroma, thus promoting cell survival, angiogenesis, invasion, evasion of immune system and metastasis. In this thesis, I investigated the role of bone marrow-derived MSCs (BM-MSCs) in tumor processes, deepening the involvement of specific signaling pathways underlying their recruitment and activity into tumor microenvironment. In particular, innovative therapeutic tools have been tested to: 1) inhibit BM-MSC-mediated growth and aggressiveness of osteosarcoma (OS) and hepatocellular carcinoma (HCC) cell lines by targeting CXCR4; 2) interfere with BM-MSC recruitment by triple negative breast cancer (TNBC) cells through modulation of PDGFRβ signaling. For the first purpose, I tested a new CXCR4 inhibitor, Peptide R, which was recently developed as an anticancer agent to overcome the toxicity of the well-known CXCR4 antagonist AMD3100. I observed a reduction in BM-MSC-mediated OS and HCC migration and invasion and a parallel decrease in BM-MSC-dependent phosphorylation of ERK and AKT. Furthermore, Peptide R, targeting and inhibiting CXCR4, prevented Epithelial Mesenchymal Transition (EMT) of OS and HCC cells promoted by BM-MSCs. For the second purpose, I used a novel aptamer-based PDGFRβ inhibitor, named Gint4.T. Aptamers, thanks to their unique characteristics (low size, good target affinity, no immunogenicity, high stability), represent a new class of molecules with a great potential to rival monoclonal antibodies in both therapy and diagnosis. I observed that Gint4.T, binding PDGFRβ, inhibited the phosphorylation of the receptor and its downstream signaling significantly preventing in vitro BM-MSC cell migration and blocking cell proliferation. Finally, I found that Gint4.T strongly reduced in vitro BM-MSC migration stimulated by two different Triple Negative Breast Cancer (TNBC) cell lines, suggesting that it could interfere with BM-MSC recruitment and their pro-tumorigenic activity within breast cancer microenvironment. Therefore, this study represents an initial development of novel tumor microenvironment-targeting therapies that, in combination with conventional approaches-oriented to tumor cells, may offer more effective alternative to treat cancer patients by targeting BM-MSCs.

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