No abstract

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Improved understanding of the mechanisms responsible for the differences between IBC and non-IBC might provide novel therapeutic targets. We studied 35 consecutive patients with IBC, biopsied prior to the initiation of chemotherapy. Angiogenesis was evaluated by Chalkley counting and by assessment of endothelial cell proliferation (ECP) and vessel maturity. The presence of fibrin, expression of the hypoxia marker carbonic anhydrase IX (CA IX) and epithelialcadherin (E-cadherin) expression were immunohistochemically detected. The same parameters were obtained in a group of 104 non-IBC patients. Vascular density, assessed by Chalkley counting (Po0.0001), and ECP (P ¼ 0.01) were significantly higher in IBC than in non-IBC. Abundant stromal fibrin deposition was observed in 26% of IBC and in only 8% of non-IBC (P ¼ 0.02). Expression of CA IX was significantly less frequent in IBC than in non-IBC with early metastasis (P ¼ 0.047). There was a significant positive correlation between the expression of CA IX and ECP in IBC (r ¼ 0.4, P ¼ 0.03), implying that the angiogenesis is partly hypoxia driven. However, the higher ECP in IBC and the less frequent expression of CA IX in IBC vs non-IBC points at a role for other factors than hypoxia in stimulating angiogenesis. Strong, homogeneous E-cadherin expression was found at cell -cell contacts in all but two IBC cases, both in lymphovascular tumour emboli and in infiltrating tumour cells, challenging our current understanding of the metastatic process. Both the intense angiogenesis and the strong E-cadherin expression may contribute to the highly metastatic phenotype of IBC.

We studied the presence of lymphangiogenesis in lymph node (LN) metastases of breast cancer. Lymph vessels were present in 52 of 61 (85.2%) metastatically involved LNs vs 26 of 104 (25.0%) uninvolved LNs (Po0.001). Furthermore, median intra-and perinodal lymphatic endothelial cell proliferation fractions were higher in metastatically involved LNs (Po0.001). This is the first report demonstrating lymphangiogenesis in LN metastases of cancer in general and breast cancer in particular. Lymph node (LN) status is the most important prognostic factor for patients with breast cancer. The presence and the extent of axillary LN metastases reflect the probability that the cancerous process has spread through the body and both are strongly correlated with the development of distant metastases and with shortened disease-free and overall survival. Lymph node metastases are more than passive tumour deposits. Metastatic tumour sites are capable of inducing a vascular stroma and can actively contribute to tumour progression and to further metastatic spread. To what extent processes involved in progression of primary tumours, such as angiogenesis and lymphangiogenesis, contribute to progression of secondary sites is largely unknown. Reports have suggested differences between primary tumours and secondary sites and between different secondary sites. Whereas primary breast tumours grow angiogenesis dependently, we demonstrated that 90% of breast cancer liver metastases grow according to an angiogenesis-independent replacement pattern (Stessels et al, 2004). The growth of breast cancer LN metastases, on the contrary, was angiogenesis dependent and angiogenesis and hypoxia in the metastases were correlated with angiogenesis and hypoxia in the primary tumours . Guidi et al (2000) demonstrated that the presence of vascular hot spots in LN metastases, but not in the primary breast tumours was associated with decreased survival.In the present study, we compared the expression of the lymphatic endothelium-specific markers Prox-1, LYVE-1 and podoplanin in metastatically involved and uninvolved LNs of patients with breast cancer. Prox-1 and LYVE-1 are, respectively, a transcription factor and a hyaluronan receptor that show specificity for lymphatic endothelial cells. D2-40 was originally described as a selective monoclonal antibody to a M r 40 000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope in lymphatic endothelium (Kahn and Marks, 2002). Recently, the D2-40 antibody has been shown to specifically recognise podoplanin, a glomerular podocyte membrane protein (Schacht et al, 2005) and has been shown to be a very sensitive and specific marker for lymphatic endothelium in most tissues (Evangelou et al, 2005) and especially in breast cancer . We investigated the presence and extent of lymphangiogenesis in LN metastases of breast cancer using the podoplanin antibody. MATERIALS AND METHODS Patients and samplesOne hundred and ten patients with operable breast cancer were included in this study, 49 patients with LN-neg...

The recognition of different subgroups of cutaneous breast cancer deposits with different degrees of hypoxia-driven angiogenesis may have important implications for the usefulness of anti-angiogenic therapy.