SCIENCE REVIEW
‘As platelet activation is a potential source of elevated VEGF, plasma VEGF may be a more accurate marker of circulating VEGF in vivo’
tumour malignancies. Bevacizumab, a monoclonal antibody directed against VEGF, has been approved for the treatment of colorectal and non-small cell lung cancer. Anti-angiogenic properties combined with normalisation of the ‘leaky’ abnormal vasculature are postulated to be factors associated with its antitumour effects. Bevacizumab is currently being evaluated in oesophagogastric cancer both for locally advanced and metastatic disease.
Endoscopic treatment has been used increasingly for T1 oesophageal squamous cell carcinoma
clinicopathological features and the study variables was for S-VEGF, which was elevated in patients with advanced T-stage (P=0.05). Circulating VEGF did not correlate with platelet count.
REVIEW OF EVIDENCE Although widely reported in squamous cell carcinoma, the role of T-VEGF in oesophageal adenocarcinoma is not as clear. A systematic review concluded that T-VEGF expression failed to give prognostic information in invasive adenocarcinoma of the oesophagus. The data presented in the Northern Ireland study identified a non- significant trend towards elevation of T-VEGF level in patients with adenocarcinoma of the oesophagus. However, ELISA assessment of T-VEGF provided no obvious prognostic benefit. The findings would concur with previous research on adenocarcinomas of the oesophagus and oesophagogastric junction; thus, the role of T-VEGF as a prognostic indicator is limited.
It has been postulated that C-VEGF may
be a reliable and easily accessible surrogate marker of angiogenic activity and tumour progression in cancer patients. Although some studies indicate that C-VEGF may be a useful predictor of survival in patients with cancer, not all studies agree. In particular, the prognostic value of C-VEGF analysis in oesophagogastric cancer remains uncertain. Such disparities have been attributed to the possibility that sources other than the tumour may contribute to VEGF level in the circulation. Vascular endothelial growth factor is
released from activated platelets ex vivo. Consequently, S-VEGF levels may be
artificially higher than in vivo levels. Such variance may depend on the total platelet level and may also reflect platelet-derived VEGF concentration, rather than being indicative of tumour derivation and actual tumour burden. It has been postulated that the apparent prognostic importance of S-VEGF may simply be a function of the platelet count, rather than the angiogenic capability of the tumour.
Analysis of plasma level, rather than that found in serum, avoids the coagulation cascade, thus restricting platelet activation. Consequently, P-VEGF rather than S-VEGF may more accurately represent tumour- derived circulating VEGF in patients with cancer. Analysis of both of these VEGF derivatives in conjunction with platelet count was undertaken by the Northern Ireland workers in an attempt to discover which, if any, had prognostic significance. The study did not demonstrate any prognostic significance for P-VEGF, S-VEGF or platelet count over a 10-year follow-up period. However, the authors acknowledged potential study limitations relating to low patient numbers, recruitment of patients with both histological tumour subtypes, and to biological variation, which may have limited the ability of the study to detect prognostic significance of VEGF in the circulation, should it exist. Recent studies continue to confirm that
circulating and tumour VEGF, in particular the vascular endothelial growth factor C subtype (a known lymphangiogenic factor), correlates with lymph node metastasis and poor prognosis in patients with squamous cell carcinoma of the oesophagus. Future treatment with anti-VEGF therapy remains a focus of research studies in solid
‘Although widely reported in squamous cell carcinoma, the role of T-VEGF in oesophageal adenocarcinoma is not as clear’
DECEMBER 2013
ORIENTAL PERSPECTIVE Endoscopic treatment has been used increasingly for T1 oesophageal squamous cell carcinoma (ESCC). However, this is sometimes incomplete if the depth of the T1 primary tumour reaches the muscularis mucosae or submucosal layer, as these tumours have a relatively high incidence of lymph node metastasis. In a recent study, a group in Osaka, Japan, looked at predictors of nodal involvement in oesophageal squamous cell carcinoma (Nakagawa Y, Ohira M, Kubo N et al. Tumour budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma. Anticancer Res 2013; 33 [11]: 5023–9), and investigated the significance of the immunohistochemical staining of C-VEGF and E-cadherin in the primary tumour and tumour budding for prediction of nodal metastasis. The Osaka group looked at 55 patients with T1 ESCC invading as deep as the submucosal layer who underwent curative oesophagectomy. Metastasis to the regional lymph nodes was observed in 26 cases (47.3%), while C-VEGF expression and reduced E-cadherin expression in the primary tumour was observed in 32 (58.1%) and 38 cases (69.1%), respectively. High-grade tumour budding was observed in 29 cases (52.7%).
E-cadherin expression and tumour budding closely correlated with nodal metastasis (P=0.04 and P<0.01, respectively), whereas C-VEGF expression tended to correlate with lymph node metastasis (P=0.06). In addition, high-grade tumour budding significantly correlated (P<0.01) with reduced E-cadherin expression. The accuracy of tumour budding and E-cadherin expression for nodal metastasis were 67.3% and 65.4%, respectively. Tumour budding (P<0.01), but not E-cadherin and VEGF-C expression, significantly correlated with poor survival.
THE BIOMEDICAL SCIENTIST 697
National Cancer Institute/Linda Bartlett
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