Presentation is loading. Please wait.

Presentation is loading. Please wait.

VEGF, recettori e sviluppo di inibitori selettivi Roma, 2-3 febbraio 2006 Raffaella Giavazzi Istituto di Ricerche Faramacologiche MarioNegri.

Similar presentations

Presentation on theme: "VEGF, recettori e sviluppo di inibitori selettivi Roma, 2-3 febbraio 2006 Raffaella Giavazzi Istituto di Ricerche Faramacologiche MarioNegri."— Presentation transcript:

1 VEGF, recettori e sviluppo di inibitori selettivi Roma, 2-3 febbraio 2006 Raffaella Giavazzi Istituto di Ricerche Faramacologiche MarioNegri

2 Angiogenesis is Required for Sustained Tumor Growth

3 Related molecules: VEGFB,C,D and placental growth factor Key mediators of angiogenesis MW 45KD Homodimeric glycoprotein Binds VEGFRs,neuropilin1, heparin Four isoform VEGF 121 VEGF 165 VEGF 186 VEGF 206 VEGF (also VEGFA)

4 VASCULAR GROWTH FACTORS & THEIR RECEPTORS Yancopoulos et al. Nature 407:242, 2000

5 Ferrara N et al Nature Reviews Cancer 2003

6 VEGF: A CENTRAL MEDIATOR OF ANGIOGENESIS Gerber and Ferrara, Cancer Res. 65, 671, 2005

7 REGULATION OF VEGF IN TUMOR CELLS by: Oncogenes (ras, src, …..) Tumor Supressor Genes (p53, vHippelLindau, PTEN…..) Activated Signaling Pathways (src, Akt/PKB,…..) Transcription Factors (HIF, NF-kB,….). Environmental Factors (hypoxia, low pH,….) Growth Factors/Cytokines & their Receptors (EGFR,IL-1,.. Hormones

8 VEGF EXPRESSION IS INDUCED BY TUMOR HYPOXIA Carmeliet & Jain, Nature 407:249, 2000 Hypoxia is a major inducer of VEGF gene expression VEGF mRNA is rapidly induced in the presence of hypoxiain in various cell type VEGF is highly expressed in tumor cells near area of necrosis

9 VEGF OVEREXPRESSION CAUSES THE FORMATION OF STRUCTURALLY AND FUNCTIONALLY ABNORMAL BLOOD VESSELS Poorly organized, tortuous, hyperpermeable Fewer pericytes Dependent on growth factors for survival and prolifertion NormalAnti-VEGFAni-VEGFTumor (VEGF) Adapted from: Jain & Carmeliet, Le Scienze 401:59, 2002

10 VEGF OVEREXPRESSION Ovary Tumor VS1 1A9 Manenti et al. Mol. Cancer Ther 2005

11 VEGF IN CANCER DEVELOPMENT AND PROGRESSION Elevated VEGF plasma levels in cancer patients Increased tumor VEGF expression associated with tumor progression and poor prognosis Highly expressed in several tumor types Brain Colon and rectum Lung Breast Kidney Bladder Ovary

12 Manenti et al.. E J Cancer, 2003 VEGF IN OVARIAN CARCINOMA PATIENTS ascites healthy non malignant ovarian carcinoma plasma VEGF pg/ml

13 VEGF IS A KEY PROANGIOGENIC FACTOR VEGF is a survival factor for newly formed vasculature VEGF is directly implicated in endothelial cell adhesion, proliferation, and migration VEGF VEGF is directly involved in proteolytic destruction of the ECM VEGF is directly involved in capillary tube formation VEGF is directly implicated in vascular permeability and vessel maturation Most therapeutic approaches to angiogenesis modulation are focused on endothelial cell functions during blood vessel formation

14 VEGF & lymphangiogenesis Lymphangiogenesis: a route of tumor metastasis stimulated by binding of VEGF-C and D to VEGFR3 promoted by VEGF interaction with VEGFR2 VEGF overexpression leads to lymphatic vessel in exp. tumors

15 Role of VEGF-C/D in lumphatic metastasis in cancer a, Tumour cells and tumour-associated macrophages secrete lymphangiogenic growth factor VEGF-C or VEGF-D, which induces sprouting of nearby lymphatic vessels, facilitating the access of tumor cells into the vessel lumen. b, Aggregates of tumour cells are transported to the regional lymph node, from which they can spread to distant organs through either blood or lymphatic vessels. Blockage of VEGFR-3 signalling inhibits metastasis in most mouse tumour xenograft models by stabilizing lymphatic vessels. c, Nude mice were implanted with luciferase-tagged tumour cells, which metastasize to the ipsilateral axillary lymph node d, By contrast, metastasis was abolished in mice treated with adenovirus encoding a VEGF-C/D trap 75. Alitalo et al.Nature 2005

16 Tumor lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival. Dadraset SS. al. Am J Path 162:1951, 2003 Lymphangiogenesis & Metastasis

17 OTHERS VEGF FUNCTIONS VEGF is implicated in intraocular neovascularization (diabetes mellitus,….age-related macular degeneration, AMD) Role of VEGF in motoneurone degeneration (amytropic lateral sclerosis, ALS)



20 Days after tumor transplant Tumor weight (mg) DC101 Vascuar index = 18 Vehicle Vascular Index = 45 % Proliferation E-09 SU 5416 (M) HUVEC HOC 1E-081E-071E-061E-051E-04 RECEPTOR TARGETING AGENTS


22 POTENTIAL EFFECTS OF INHIBITING VEGF Prevention of the growth of new tumor blood vessels suppression of primary and metastatic tumor growth Regression of tumor vasculature and restoration of vascular permeability and intratumoral pressure improved access for other anticancer agents (and O 2 ) Vascular regression possible tumor dormancy From : Jain RK. Nat Med 2001; Willett CG, et al. Nat Med 2004


Download ppt "VEGF, recettori e sviluppo di inibitori selettivi Roma, 2-3 febbraio 2006 Raffaella Giavazzi Istituto di Ricerche Faramacologiche MarioNegri."

Similar presentations

Ads by Google