Cancer Res Treat.  2006 Dec;38(4):189-197.

Tumor Angiogenesis: Initiation and Targeting : Therapeutic Targeting of an FGF-Binding Protein, an Angiogenic Switch Molecule, and Indicator of Early Stages of Gastrointestinal Adenocarcinomas

• Tassi E
• Wellstein

Abstract

Tumor angiogenesis has been related to the initiation as well as progression toward more aggressive behavior of human tumors. In particular, the activity of angiogenic factors is crucial for tumor progression. We previously characterized a secreted fibroblast growth factor-binding protein (FGF-BP) as a chaperone molecule, which binds to various FGFs, enhances FGF-mediated biochemical and biologic events and importantly is a crucial rate-limiting factor for tumor-dependent angiogenesis. We generated monoclonal antibodies that target FGF-BP protein and used them as a tool to evaluate frequency and pattern of FGF-BP expression during the malignant progression of pancreas and colorectal carcinoma in archival tissue samples. We found that FGF-BP is dramatically upregulated during the initiation of colorectal and pancreatic adenocarcinoma. Crucial genetic events underlying the initiation and progression of colorectal and pancreatic adenocarcinoma with a particular focus on the modulation of angiogenesis and antiangiogenic therapies are discussed. We propose that the upregulation of the secreted FGF-BP protein during early phases of pancreas and colon cancer could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions. Furthermore, the biological activity of FGF-BP is neutralized by monoclonal antibodies suggesting the potential for antibody-based therapeutic targeting.

Keyword

FGF-binding protein; Colonic neoplasms; Pancreatic neoplasms; Tumor angiogenesis; Antiangiogenic agents

MeSH Terms

Adenocarcinoma*
Angiogenesis Inducing Agents
Angiogenesis Inhibitors
Antibodies, Monoclonal
Biomarkers
Colonic Neoplasms
Colorectal Neoplasms
Fibroblasts
Humans
Pancreas
Pancreatic Neoplasms
Staphylococcal Protein A
Up-Regulation
Angiogenesis Inducing Agents
Angiogenesis Inhibitors
Antibodies, Monoclonal
Staphylococcal Protein A

Figure

• 

  Fig. 1 Genetic alterations during the development of colorectal cancer. Significant genetic alterations at different junctures during the transformation of colon epithelia to invasive adenocarcinoma are depicted. Induction of FGF-BP expression is an early event that is driven by mutations and activation of the WNT/beta-catenin pathway (Adapted and modified from Tassi E. and Wellstein A., Sem. Onc., in press).

• 

  Fig. 2 Genetic alterations during malignant transformation of pancreas epithelia. The progression from normal duct epithelium to low-grade and high-grade PanIN (Pancreatic Intraepithelial Neoplasia) and the associated accumulation of genetic alterations are shown (Adapted and modified from Tassi E. and Wellstein A., Sem. Onc., in press).

• 

  Fig. 3 FGF-BP expression in human and mouse dysplastic lesions. (A) Frequency of FGF-BP protein expression, analyzed by immunohistochemistry (IHC) with a polyclonal anti-FGF-BP antibody in 161 human specimens ***P<0.0001. (B) Frequency of FGF-BP mRNA expression in normal and dysplastic intestinal tissues obtained from B6 APCMin/+ mice. FGF-BP expression coincides with the activation of the beta-catenin pathway in this model **P<0.001 (36) (Adapted and modified from Tassi E. and Wellstein A., Sem. Onc., in press).

• 

  Fig. 4 Characterization of FGF-BP monoclonal antibodies. (A) and (B) ELISA assay with mouse monoclonal antibodies to human FGF-BP. (A) specificity of the mAbs. Recombinant FGF-BP (50 ng/well) was immobilized in a microtiter plate and detected with different concentrations of mAbs indicated. (B) sensitivity of the mAb. Different concentrations of recombinant FGF-BP were immobilized and incubated with 0.2µg/ml of the mAbs indicated. (C) Western blot analysis of FGF-BP from frozen surgical samples of colon and head and neck (H/N) cancer tissues and ME180 xenografts. N=normal tissue. (D) Immunofluorescence of FGF-BP transiently transfected SW13 cells. Only some of SW13 transfected cells express detectable FGF-BP protein (green) and the F-actin stain highlights all cells (red) (Adapted and modified from (37)).

• 

  Fig. 5 FGF-BP staining in premalignant human colon and pancreas lesions. (A) Histochemistry with a monoclonal antibody against FGF-BP shows expression (dark brown staining) in dysplastic lesions of the colon next to normal crypt epithelia (N). (B) A serial section from panel A stained with the secondary antibody only. (C) FGF-BP staining in a PanIN lesion. (D) A normal pancreatic duct shows no staining for FGF-BP. Further details in Ref. (37) (Adapted and modified from Tassi E. and Wellstein A., Sem. Onc., in press).

• 

  Fig. 6 Growth inhibition by a monoclonal Ab to FGF-BP. Soft agar colony formation of SW13/FGF-BP or mock transfected SW13 cells treated with the 4E7 mAb (40µg/ml). The number of colonies is given in the abscence and presence of FGF-2±the mAb (Adapted and modified from (37)).

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