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  • P Journal of 10.4172/2161-1459.1000e118 Clinical and ...€¦ · Botti et al., Clin Exp Pharmacol 2012, 2:3 DOI: 10.4172/2161-1459.1000e118. Editorial. Open Access. Clin Exp Pharmacol
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Botti et al., Clin Exp Pharmacol 2012, 2:3 DOI: 10.4172/2161-1459.1000e118 Open Access Editorial Volume 2 • Issue 3 • 1000e118 Clin Exp Pharmacol ISSN: 2161-1459 CPECR, an open access journal Extracellular Matrix Molecules as Targets for Melanoma Therapy Gerardo Botti*, Margherita Cerrone, Annamaria Anniciello, Rossella De Cecio, Paolo Ascierto, and Monica Cantile National Cancer Institute-Fondazione Pascale, Naples, Italy Abstract Malignant melanoma, between human diseases, represents a best model to study tumor progression process. In fact, during its evolution, a series of events takes place involving several molecular mechanisms associated to both melanocytes transformation and to the surrounding microenvironment, with a prevalent involvement of Extracellular Matrix (ECM). A large series of mechanisms correlated to the activity of these molecules have been studied to establish specific interfering system for target therapies in several human cancers. We suggest that the combination of specific ECM target therapies and immune-therapy, making more efficient the therapeutic approaches for malignant melanoma disease. *Corresponding author: Gerardo Botti, Department of Pathology, National Cancer Institute-Fondazione Pascale, Naples, Italy, Tel +39 081 5903766; Fax: +39 081 5903718; E-mail: [email protected] Received November 21, 2012; Accepted November 23, 2012; Published November 26, 2012 Citation: Botti G, Cerrone M, Anniciello A, De Cecio R, Ascierto P, et al. (2012) Extracellular Matrix Molecules as Targets for Melanoma Therapy. Clin Exp Pharmacol 2:e118. doi:10.4172/2161-1459.1000e118 Copyright: © 2012 Botti G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Editorial e incidence of melanoma is gradually growing around the world, with particular increase among young individuals. e out-of- control cell growth and the loss of cellular homeostasis play a key role in the genesis and progression of the tumor. At junction level these mechanisms control the proliferation, differentiation and apoptosis of melanocytes. In particular, interactions between transformed cells and transformed cell with extracellular matrix are crucial for melanoma progression. Molecules of the extracellular matrix in tumor micro- environment are responsible for tumor progression. erefore, in order to establish specific target therapies, it is extremely important to set up molecular models which inhibit their activity. Several studies have proved, for various tumor typologies, the possibility either to inhibit or interfere with the function of these molecules, both in vitro and in vivo. e inhibition can take place at gene transcription level, using specific siRNA, as well as at protein level using specific antibodies against ECM proteins [1-7]. Silencing, employing specific siRNA, causes a reduction in cell proliferation, colony formation and invasiveness of tumor cells in vitro as demonstrated by Dong et al. [8] and Shen et al. [9] on metallo proteinases investigations. Besides in vitro studies carried out on cell models of melanoma have shown that the down-regulation by siRNA technique of MMP13 strongly enhanced pigmentation of melanocytes as well as a decreasing in cell proliferation [10]. MMP-2 silencing, through adenovirus-mediated and siRNA techniques in spinal metastatic melanoma model, significantly inhibits tumor growth and results in a complete retention of neurological function in animals [11]. Several molecules have been considered capable of inhibiting MMPs catalytic activity, especially pseudopeptides and non-peptidic molecules, which selectively bind themselves to zinc-bing site of these proteins. Batimostat, barimostat, AG3344 and bay-219566 are the most used molecules at present [12]. Many integrin-inhibitors have also been set up. ey have a strong capacity of inhibiting the progression of neoplastic cells as shown by studies on animal models. In particular, Cyclic RGD peptides have been synthetized, which selectively inhibit alpha v integrins [13,14]. Synthetic peptides against alpha5beta1 and alphavbeta3 integrins are now days employed in pre-clinical studies [15-17]. “Disintegrins” represent another category of integrin inhibitors. ey are small non- enzymatic proteins with the capacity of interacting with many cell types, including melanoma cells. Salmosin, Jararhagin, Eristostatin, Contortrostatin and Obtustatin are the most studied and used “disintegrins” [18-22]. Anti-integrin antibodies have also been obtained (targeting alpha vs. integrins in particular): in mice model, Vitaxin and CNT095 strongly inhibit the growth of melanoma tumors [23]. e employment of RNA interference (siRNA), blocking Osteopontin (OPN) expression in melanoma cells, reduces cells number and invasiveness [24], whereas in other tumors, the employment of siRNA against OPN transcript causes a consistent suppression of tumorigenicity in vitro [25]. Beside, blocking of OPN expression can down-regulate other ECM molecules, specifically some metallo proteinases [26]. In recent years, several molecules have been identified as inhibitors of OPN, in particular Agelastatin A, an alkaloid with high anti-tumor efficacy [27]. Humanized monoclonal antibodies blocking OPN have been lately targeted: ASK 8007, is very efficacious in patients with rheumatoid arthritis [28] and anti-human OPN antibody 1A12 is used in breast cancer treatment [29]. Regarding SPARC (Osteonectin) silencing, it has been shown that anti-sense expression vector in melanoma cells is capable of reducing the invasive and adhesive capacity of tumor cells [30]. Moreover, siRNA blocking SPARC expression in cell and animals models of melanoma, inhibits cell growth with G (1) arrest induction [31]. In uveal melanoma too, OPN silencing is capable of reducing tumor cells proliferation [32]. Small peptides have been recently synthesized. eir molecular structure is very simple, capable of binding different SPARC protein domains, blocking angiogenesis and inhibiting tumor growth as shown in animal models [33,34]. Journal of Clinical and Experimental Pharmacology J o u r n a l o f C l i n i c a l & E x p e r i m e n t a l P h a r m a c o l o g y ISSN: 2161-1459

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  • Botti et al., Clin Exp Pharmacol 2012, 2:3DOI: 10.4172/2161-1459.1000e118

    Open AccessEditorial

    Volume 2 • Issue 3 • 1000e118Clin Exp PharmacolISSN: 2161-1459 CPECR, an open access journal

    Extracellular Matrix Molecules as Targets for Melanoma TherapyGerardo Botti*, Margherita Cerrone, Annamaria Anniciello, Rossella De Cecio, Paolo Ascierto, and Monica Cantile

    National Cancer Institute-Fondazione Pascale, Naples, Italy

    AbstractMalignant melanoma, between human diseases, represents a best model to study tumor progression process. In

    fact, during its evolution, a series of events takes place involving several molecular mechanisms associated to both melanocytes transformation and to the surrounding microenvironment, with a prevalent involvement of Extracellular Matrix (ECM).

    A large series of mechanisms correlated to the activity of these molecules have been studied to establish specific interfering system for target therapies in several human cancers. We suggest that the combination of specific ECM target therapies and immune-therapy, making more efficient the therapeutic approaches for malignant melanoma disease.

    *Corresponding author: Gerardo Botti, Department of Pathology, National Cancer Institute-Fondazione Pascale, Naples, Italy, Tel +39 081 5903766; Fax: +39 081 5903718; E-mail: [email protected]

    Received November 21, 2012; Accepted November 23, 2012; Published November 26, 2012

    Citation: Botti G, Cerrone M, Anniciello A, De Cecio R, Ascierto P, et al. (2012) Extracellular Matrix Molecules as Targets for Melanoma Therapy. Clin Exp Pharmacol 2:e118. doi:10.4172/2161-1459.1000e118

    Copyright: © 2012 Botti G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    EditorialThe incidence of melanoma is gradually growing around the

    world, with particular increase among young individuals. The out-of-control cell growth and the loss of cellular homeostasis play a key role in the genesis and progression of the tumor. At junction level these mechanisms control the proliferation, differentiation and apoptosis of melanocytes. In particular, interactions between transformed cells and transformed cell with extracellular matrix are crucial for melanoma progression. Molecules of the extracellular matrix in tumor micro-environment are responsible for tumor progression. Therefore, in order to establish specific target therapies, it is extremely important to set up molecular models which inhibit their activity.

    Several studies have proved, for various tumor typologies, the possibility either to inhibit or interfere with the function of these molecules, both in vitro and in vivo. The inhibition can take place at gene transcription level, using specific siRNA, as well as at protein level using specific antibodies against ECM proteins [1-7].

    Silencing, employing specific siRNA, causes a reduction in cell proliferation, colony formation and invasiveness of tumor cells in vitro as demonstrated by Dong et al. [8] and Shen et al. [9] on metallo proteinases investigations. Besides in vitro studies carried out on cell models of melanoma have shown that the down-regulation by siRNA technique of MMP13 strongly enhanced pigmentation of melanocytes as well as a decreasing in cell proliferation [10].

    MMP-2 silencing, through adenovirus-mediated and siRNA techniques in spinal metastatic melanoma model, significantly inhibits tumor growth and results in a complete retention of neurological function in animals [11].

    Several molecules have been considered capable of inhibiting MMPs catalytic activity, especially pseudopeptides and non-peptidic molecules, which selectively bind themselves to zinc-bing site of these proteins. Batimostat, barimostat, AG3344 and bay-219566 are the most used molecules at present [12].

    Many integrin-inhibitors have also been set up. They have a strong capacity of inhibiting the progression of neoplastic cells as shown by studies on animal models. In particular, Cyclic RGD peptides have been synthetized, which selectively inhibit alpha v integrins [13,14]. Synthetic peptides against alpha5beta1 and alphavbeta3 integrins are now days employed in pre-clinical studies [15-17]. “Disintegrins” represent another category of integrin inhibitors. They are small non-enzymatic proteins with the capacity of interacting with many cell types, including melanoma cells. Salmosin, Jararhagin, Eristostatin,

    Contortrostatin and Obtustatin are the most studied and used “disintegrins” [18-22].

    Anti-integrin antibodies have also been obtained (targeting alpha vs. integrins in particular): in mice model, Vitaxin and CNT095 strongly inhibit the growth of melanoma tumors [23].

    The employment of RNA interference (siRNA), blocking Osteopontin (OPN) expression in melanoma cells, reduces cells number and invasiveness [24], whereas in other tumors, the employment of siRNA against OPN transcript causes a consistent suppression of tumorigenicity in vitro [25]. Beside, blocking of OPN expression can down-regulate other ECM molecules, specifically some metallo proteinases [26].

    In recent years, several molecules have been identified as inhibitors of OPN, in particular Agelastatin A, an alkaloid with high anti-tumor efficacy [27]. Humanized monoclonal antibodies blocking OPN have been lately targeted: ASK 8007, is very efficacious in patients with rheumatoid arthritis [28] and anti-human OPN antibody 1A12 is used in breast cancer treatment [29].

    Regarding SPARC (Osteonectin) silencing, it has been shown that anti-sense expression vector in melanoma cells is capable of reducing the invasive and adhesive capacity of tumor cells [30]. Moreover, siRNA blocking SPARC expression in cell and animals models of melanoma, inhibits cell growth with G (1) arrest induction [31]. In uveal melanoma too, OPN silencing is capable of reducing tumor cells proliferation [32].

    Small peptides have been recently synthesized. Their molecular structure is very simple, capable of binding different SPARC protein domains, blocking angiogenesis and inhibiting tumor growth as shown in animal models [33,34].

    Journal ofClinical and Experimental PharmacologyJourna

    l of C

    linica

    l & Experimental Pharm

    acology

    ISSN: 2161-1459

  • Citation: Botti G, Cerrone M, Anniciello A, De Cecio R, Ascierto P, et al. (2012) Extracellular Matrix Molecules as Targets for Melanoma Therapy. Clin Exp Pharmacol 2:e118. doi:10.4172/2161-1459.1000e118

    Page 2 of 2

    Volume 2 • Issue 3 • 1000e118Clin Exp PharmacolISSN: 2161-1459 CPECR, an open access journal

    The effects of both siRNA [35] and monoclonal antibodies against different domains of Tenascin C protein has also been investigated [36].

    Finally, CCN3 protein expression is in reverse correlation to neoplastic progression of melanoma. Many experiments on both induction and silencing of CCN3 have been carried out and the results have shown a subsequent alteration of adhesion capacity to laminin and vitronectin [37].

    It is then feasible to assume that the improvement and progression of therapeutic approaches for melanoma could be achieved by the integration of specific therapies against ECM molecules combined with immunotherapy.

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    TitleCorresponding authorAbstractEditorialReferences


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Nanoemulsion Based Targeting in Cancer Therapeutics · Praveen Kumar G, Divya A (2015) Nanoemulsion Based Targeting in Cancer Therapeutics. Med chem 5: 272-284. doi: 10.4172/2161-0444.1000275

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Entomology, rnithology & Herpetology - Longdom · Entomology, rnithology & Herpetology Freitag, Entomol Ornithol Herpetol 2015, 4:4 DOI: 10.4172/2161-0983.1000166 Entomol Ornithol

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