We read with great interest the paper by Heer et al., (1) published recently in Clinical Cancer Research. In their paper, the authors show serum VEGF1 is elevated in patients with breast cancer compared with normal healthy control subjects. However, questions have been raised over the accuracy of using serum VEGF as a marker, with the observation that VEGF is released from platelets during venepuncture (2, 3). Studies have additionally shown that the association of high serum levels of VEGF with poor prognosis in cancer patients may be correlated with an elevated platelet count (4). We have addressed this by comparing VEGF in serum and plasma in a cohort of breast cancer patients and matched controls. Using a cohort matched for size and geographical location we showed that plasma VEGF and not serum VEGF is increased compared with controls in breast cancer patients (5).
The observation by Heer et al. (1) that serum VEGF levels were increased in patients with invasive ductal carcinomas but not invasive lobular carcinomas is in keeping with previous observations of a difference in VEGF protein expression between these two biologically distinct tumor types (6). Indeed, the lack of an association between immunohistochemically detected VEGF protein expression and microvessel density in lobular carcinomas suggests the possibility of dissociation between VEGF production and angiogenesis in these tumours.
The observation by Heer et al. (1) of a marked increase in serum VEGF with ductal carcinoma in situ is of great interest given recent suggestions that angiogenesis is important in the transition from preinvasive to invasive disease and the potential for therapeutic intervention with antiangiogenic agents (7). Given the possibility that invasive diagnostic procedures may result in platelet activation and elevate serum rather than plasma VEGF, it would be interesting to know whether there was any possibility that preoperative hookwire insertion could have influenced the serum levels.
The authors showed a correlation between VEGF and ER (-α?) positivity but dismiss the possibility of a steroid promoter(s) in the VEGF response element. We would like to point out that the VEGF gene contains consensus estrogen response elements both at the 5′ and 3′ ends (8). Furthermore, there is accumulating evidence of an inhibitory relationship between ERα expression and production of angiogenic factors, with the observation of down regulation of VEGF in breast cancer xenografts engineered to overexpress ERα (9).
VEGF is arguably the single most important angiogenic factor identified to date. Until the factors influencing its expression are better understood, determination of blood levels will be of limited diagnostic or prognostic use in the clinic.
The abbreviations used are: VEGF, vascular endothelial growth factor; ER, estrogen receptor.
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