β Scribed by George W. Sledge Jr; Kathy D. Miller
No coin nor oath required. For personal study only.
and poor tumor differentiation. In addition, Linderholm's data suggest that VEGF production is associated with an increased risk of brain and visceral metastasis, a finding confirmed by Foekens et al. 14 Although perhaps best studied in breast cancer, the number of cancers in which VEGF tissue expression has been correlated with impaired prognosis is truly impressive and includes (but probably is not limited to) bladder cancer, 15 esophageal cancer, 16 gastric cancer, 17 prostate cancer, 18 acute myelogenous leukemia, 19 head and neck cancer, 20,21 soft tissue sarcoma, 22 osteosarcoma, 23 non-small cell lung cancer, 24-27 papillary thyroid cancer, 28 cervical cancer, 29,30 ovarian cancer, 31 pancreatic cancer, 32 and glioma. 33 The literature surrounding this association is as vast as it is confusing, with great variation in technique, reagents, and scoring. A significant number of these trials are characterized by small numbers of patients and varying disease stage and histopathologic type. Taken together, they represent impressive support for the relationship between VEGF expression and patient outcome, yet are of uncertain value for the practicing clinician.
Although most studies of the prognostic effects of the VEGFs have focused on the parent (VEGF) ligand, emerging evidence suggests that VEGF-B and VEGF-C may play a role in breast cancer (Fig 1). VEGF-B, like VEGF, acts as a ligand for VEGFR-1, although not (unlike VEGF) for VEGFR-2. In vitro data suggest that activation of VEGFR-1 by VEGF-B is only weakly mitogenic for endothelial cells. A recent publication by Gunningham et al 34 suggests that VEGF-B over-expression is associated with lymph node metastasis but not angiogenesis. This trial was not powered to determine the effect of VEGF-B expression on overall survival.
VEGF-C is the ligand for VEGFR-3. This ligand-receptor complex is believed to play a role in lymphangiogenesis. Karpanen et al 35 have recently demonstrated that VEGF-C transfection of MCF-7 breast cancer cells promoted the growth of tumor-associated lymphatic vessels, which in the tumor periphery were commonly infiltrated with the tumor cells. Related experiments in an orthotopic model demonstrated that VEGF-C overexpression resulted in significantly enhanced metastasis to regional lymph nodes and to lungs; the degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. 36 It is unsurprising that VEGF-C is expressed in many invasive breast cancers 37 and that its overexpression is associated with lymphatic vessel invasion and (in one small study) disease-free survival. 38 Angiopoietin/Tie-2. The angiopoietin/Tie-2 ligand-receptor complex also plays an important role in physiologic and pathologic angiogenesis,
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## Abstract Angiogenesis is essential for the development and growth of tumors. It is a highly regulated process that requires crossβtalk between signaling pathways at all stages of blood vessel development and tumor growth, from the recruitment of endothelial cells to vessel maturation. This revie