Clinical impact and network of determinants of tumour necrosis in colorectal cancer
CD105 and its ligand transforming growth factor β (TGFβ) are modulators of angiogenesis, which drives tumour growth and metastasis. Tumour microvessel density (MVD) has proven to be an important determinant of prognosis. In this study, we have examined the prognostic value of MVD identified using Mabs to the pan-endothelial marker CD34 and to CD105 in 111 patients with colorectal cancer. The Mab to CD105 preferentially reacts with angiogenic endothelial cells. Of the 111 patients studied, 38 were alive and 73 had died of the disease. The median MVD values counted using anti-CD34 and anti-CD105 were 5 (range 1.40–9.00) and 3.10 (range 0.90–8.00), respectively. Kaplan–Meier survival analysis revealed that only MVD values obtained using CD105 Mab correlated with survival. Patients with a high MVD, above the median (3.10), showed the worst prognosis. A similar outcome was observed when MVD was divided into quartiles. In order to ascertain if this strong expression of CD105 in the tumour vasculature is reflected in patients' plasma, circulating levels of CD105, TGFβ1 and TGFβ3 together with the receptor–ligand complexes were quantified in patients with colorectal carcinoma and normal controls. Results showed that except for TGFβ1, the levels of all other molecules were significantly elevated compared with controls. The levels of CD105 were positively correlated with Dukes' stages. A lower TGFβ1 level was noted in patients with carcinoma over the controls. Furthermore, TGFβ3 and CD105/TGFβ3 complexes were markedly lowered in postoperative compared with preoperative plasma samples. Immunostaining revealed that TGFβ1 was expressed in cancer cells but TGFβ3 in the stromal cells, whereas CD105 was exclusively expressed in vascular endothelial cells of tumour blood vessels. In conclusion, this study demonstrates that MVD quantified using a Mab to CD105 is an independent prognostic parameter for survival of patients with colorectal cancer, and that plasma levels of CD105, TGFβ1, TGFβ3 and CD105/TGFβ complexes may be useful markers for assessing disease progression. These data have led us to propose that quantification of these determinants may prove useful to monitor therapeutic efficacy in patients with colorectal cancer, especially those who are being treated with antiangiogenic therapies.