Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ

Abstract

The objective of this study was to investigate expression of various growth factors associated with angiogenesis and lymphangiogenesis and of their receptors in ductal carcinomas in situ of the breast (DCIS). We studied protein expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)-A, endothelin (ET)-1, and VEGF-C, and their receptors bFGF-R1, Flt-1, KDR, ET A R, ET B R, and Flt-4 immunohistochemically in 200 DCIS (pure DCIS: n ¼ 96; DCIS adjacent to an invasive component: n ¼ 104) using self-constructed tissue microarrays. Basic fibroblast growth factor-R1, VEGF-C, Flt-4, and ET A R were expressed in the tumour cells in the majority of cases, whereas bFGF and Flt-1 expression was rarely observed. VEGF-A, KDR, ET-1, and ET B R were variably expressed. The findings of VEGF-C and its receptor Flt-4 as lymphangiogenic factors being expressed in tumour cells of nearly all DCIS lesions and the observed expression of various angiogenic growth factors in most DCIS suggest that in situ carcinomas are capable of inducing angiogenesis and lymphangiogenesis. Moreover, we found a higher angiogenic activity in pure DCIS as compared to DCIS with concomitant invasive carcinoma. This association of angiogenic factors with pure DCIS was considerably more pronounced in the subgroup of non-high-grade DCIS (n ¼ 103) as compared with high-grade DCIS (n ¼ 94). Determination of these angiogenic markers may therefore facilitate discrimination between biologically different subgroups of DCIS and could help to identify a particularly angiogenic subset with a potentially higher probability of recurrence or of progression to invasiveness. For these DCIS, targeting angiogenesis may represent a feasible therapeutic approach for prevention of progression of DCIS to invasion.

Vascular Endothelial Growth Factor Receptors VEGFR-2 and VEGFR-3 Are Localized Primarily to the Vasculature in Human Primary Solid Cancers

“…In contrast to our data, all previous NSCLC studies report that VEGFR-2 is predominantly (48-100%) found on malignant cells (18,19,25), although vessel expression is also observed in some (18,19). Similar to our findings, VEGFR-2 has previously been localized to vessels, supporting BCs (16,17); however, there is only one report of upregulation on vessels (16) and the majority of other studies claim a breast tumor cell localization (22)(23)(24). Similar VEGFR-3 vascular expression data have been reported for BCs (27)(28)(29)(30) and NSCLCs (31); however, others report localization of VEGFR-3 to malignant breast (23,35) or lung cells (19,25,32,33,36,37).…”

“…In our hands, the VEGFR-2 antibodies 55B11, A3, sc-315, and sc-504 commonly used to investigate the expression of VEGFR-2 in human tumors (18)(19)(20)(21)(22)(23)(24), did not qualify as specific. All three detected multiple bands, running at different sizes to that expected for VEGFR-2, in lysates prepared from cell lines expressing VEGFR family members (Fig.…”

“…one or the other receptor to tumor vessels (15,16,24,(26)(27)(28)(29)(30)(31), the majority report expression in malignant cells (18)(19)(20)(21)(22)(23)(24)(25)(32)(33)(34)(35)(36)(37). Antibodies from a single source have been used to produce the majority of data, suggesting that tumor cells express VEGFR-2.…”

“…However, tumor cell expression has also been reported in 40% to 100% of CRC (20,21), BC (22)(23)(24), and NSCLC (18,19,25). Similarly, some reports confine VEGFR-3 to tumor vessels, primarily lymphatic but also blood endothelium in CRC (26), BC (27)(28)(29)(30), and NSCLC (19,(31)(32)(33), whereas others localize the receptor to tumor cells [CRC (34), BC (23,35), and NSCLC (19,25,32,33,36,37)]. Recently, Petrova et al (38) have provided compelling evidence that poor antibody specificity is likely to be responsible for some of the claims that VEGFR-3 is found on human tumor cells (38).…”

Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer

“…Details on patients' characteristics have been described previously (Wülfing et al, 2003 and2005a). In addition, in 24 lymph nodepositive patients we selected the corresponding lymph node metastases for analysis of PRL-3 expression.…”