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Thread: aFGF as target in antiangiogenic tumor therapy

  1. #1 aFGF as target in antiangiogenic tumor therapy 
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    Mar 2009

    In Oktober 2008 I had to write a review about an angiogenic Factor called aFGF or acidic fibroblast growth factor which is a new target in anti-tumoral therapy as they can induce neo-angiogenesis by overproduction of aFGF and aFGF receptor

    If you are interested... It is a general overview and I hope it ain't to difficult to understand. If you have any questions or feedback please don't hesitate to contact me

    FGF-1; Antiangiogenic therapy against Cancer?

    Physiologically the acidic Fibroblast growth Factor, also known as FGF-1 is involved in angiogenesis, tissue repair and wound healing. Earlier studies have shown that FGFs also have oncogenic potential as tumors abuse them to induce angiogenesis for their blood support. This knowledge is used to create new therapies against cancer- via inhibition of FGF-1 induced angiogenesis. (1-4)
    In humans the Fibroblast Growth factors can be differed in 7 families. Generally the FGFs bind to a family of tyrosine-kinase surface cell receptors called FGFRs. (1-4). (1)
    Role of FGF-1 in angiogenesis
    The FGFs also have a binding site for heparin and heparin sulphate proteoglycans. As they stabilize the receptor-ligand complex heparin and heparansulphate are involved in binding of FGF to the FGFR. After the binding of FGF to the FGFR the receptor dimerizes and induces autophosphorylation of the receptor tyrosine kinase. In the next step the RAS-MAPK pathway, the PLCγ-PKC, the PI3K-Akt and the p38-MAPK pathways can be induced. These pathways are the prerequisite for the cell division. (5, 6)
    Another factor is that FGF1 (also FGF2 and FGF4) upregulate the production of uPA and MMPís in epithelial cells. They also modulate the expression of the uPA receptor on the cell surface.(7) The uPA or urokinase-type Plasminogen activator is serine-protease and it activates plasmin through binding plasminogen. This induces fibrinolysis. MMPs are so called Matrix metalloproteinases and they are capable of degrading all kinds of extracellular matrix. They can be activated when new blood vessels have to grow.
    The physiological relevance of this observation was proven in a pre-clinical trial on mice published in 2007. The animals were treated intratumorally with either one or six injections of VEGF, FGF-1 or saline (6microgr/ mouse). 24 hours after the last injections the tumors were removed. It turned out that only the treatment with the FGF-1 and only in the 6 dose group significantly increased tumor size and weight. (8)
    Antitumoral therapy
    An interesting strategy in anti-tumor therapy is to combine cytotoxic chemotherapy drugs with factors inhibiting angiogenesis. Such an approach was shown in a trial, where mice representing a colon adenocarcinoma model, were treated with a combination of a recombinant FGFR-1 and low dose gemcitabine (as chemotherapy).
    This combination therapy resulted in a decreased tumor volume, microvessel density, tumor cell proliferation and an increase of apoptosis.(9)
    Furthermore, monoclonal antibodies against FGF-1 have been tested, but the problem was that these antibodies very often caused an immune response. Indeed humanized or chimeric antibodies have fewer side effects than the monoclonal antibodies but there are still some problems associated with it. Another possibility in anticancer therapy might be to link drug molecules or radioisotopes to the specific growth factor because tumors also over-express the Growth-factor receptors. This would mean a targeted application of a cytotoxic compound specifically to the tumor micro-environment. (10)

    FGF-1 as marker
    In 1998 the role of FGF-1 as a tumor marker was investigated.
    It was found that especially in patients with breast cancer the FGF-1 and the FGFR proteins could be found in the serum. Significantly only in malign tumors the samples of the patientsí mammary vessels were positive. To detect the proteins, a specific antibody was used, that didnít cross-interfere with the FGF-2 protein. This trial showed that not only paracrine but also autocrine stimulation plays a role in tumorigenesis.(11)

    1. Zakrzewska M, Marcinkowska E, Wiedlocha A. FGF-1: from biology through engineering to potential medical applications. Crit Rev Clin Lab Sci 2008; 45: 91-135.
    2. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20: 563-9.
    3. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7: 165-97.
    4. Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993; 60: 1-41.
    5. Boilly B, Vercoutter-Edouart AS, Hondermarck H, Nurcombe V, Le Bourhis X. FGF signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev 2000; 11: 295-302.
    6. Sorensen V, Wiedlocha A, Haugsten EM, Khnykin D, Wesche J, Olsnes S. Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail. J Cell Sci 2006; 119: 4332-41.
    7. Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des 2007; 13: 2025-44.
    8. Okunieff P, Sun J, Fenton B, Liu W, Ding I. Intratumoral VEGF and FGF1 administration alters tumor growth, vascular density, oxygenation, and expression of MCP-1 and interleukins. Adv Exp Med Biol 2007; 599: 109-16.
    9. Zheng SJ, Zheng SP, Huang FY, Jiao CL, Wu RL. Synergistic anti-tumor effect of recombinant chicken fibroblast growth factor receptor-1-mediated anti-angiogenesis and low-dose gemcitabine in a mouse colon adenocarcinoma model. World J Gastroenterol 2007; 13: 2484-9.
    10. Marcinkowska E, Superat K, Wiedlocha A. FGF-1 as a possible carrier for targeted drug delivery. Oncol Res 2006; 16: 27-34.
    11. Yoshimura N, Sano H, Hashiramoto A, et al. The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer. Clin Immunol Immunopathol 1998; 89: 28-34.

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