Angiopoietin‐2 expression in breast cancer correlates with lymph node invasion and short survival

Abstract

Angiogenic factors produced by tumor cells are essential for tumor growth and metastasis. In our study, the expression of Angiopoietin-1 (ANG1) and Angiopoietin-2 (ANG2) mRNA in archival human breast cancer tumor samples and in 6 breast cancer cell lines was investigated. Total RNA from biopsies of 38 breast cancer patients was extracted and ANG1 and ANG2 mRNA expression was measured by means of quantitative real-time RT-PCR (Taqmanா). Matching data with available clinicopathologic and biochemical data revealed a significant association between ANG2 expression and axillary lymph node invasion. Univariate and multivariate survival analysis, by means of Kaplan-Meier method and Cox's proportional hazards model, showed significant and independent association between ANG2 mRNA level and both disease-free (p < 0.0001) and overall survival (p < 0.0003). An important fact is that, notwithstanding the small number of cases examined, this association was confirmed also in the group of lymph node-negative patients (DFS, p < 0.003; OS, p < 0.020). Immunohistochemical analysis demonstrated that Ang2 is expressed by both tumor cells and endothelial elements. Expression in tumor cells was confirmed by studying a panel of human breast carcinoma cell lines in culture by RT-PCR. In ZR75.1 and T47D cells, expression of ANG2 mRNA was increased up to 10-fold by treatment with estrogen within 24 hr. Although preliminary, these data suggest a possible role of ANG2 as a prognostic factor for primary breast cancer.

Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer

“…The prognostic significance of Ang-1 and Ang-2 in breast cancer is still unclear. Overexpression of Ang-2 correlated with poor prognosis in several tumors [25][26][27] including breast cancer, 28 whereas other studies were discordant. 6,29 Similarly, the role of Ang-1 as a prognostic marker in tumors is uncertain.…”

Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer

“…The Ang-2 knockout perinatal mouse showed defects in the overall organization of their lymphatic vasculature, and Ang-2 was thought to relate to lymphatic vessel formation or lymphangiogenesis (20). A correlation between lymph node involvement and Ang-2 expression was found in colon and breast carcinomas (21,22), but is controversial (23). VEGF and/or VEGF-C expression was reported to be present in tumors overexpressing Ang-2 (22).…”

“…A correlation between lymph node involvement and Ang-2 expression was found in colon and breast carcinomas (21,22), but is controversial (23). VEGF and/or VEGF-C expression was reported to be present in tumors overexpressing Ang-2 (22). Another study, however, presents that VEGF-C plays a role in the early stage of lymphatic vessel formation, and Ang-2 plays a role in the later remodeling stages (20).…”

The enigmatic role of angiopoietin-1 in tumor angiogenesis

“…In general, high levels of Ang2 by tumor or vascular tissues have been documented in a wide variety of highly vascularized tumors such as malignant glioblastoma [54][55][56], nonsmall cell lung cancer [57,58], hepatocellular carcinoma [59][60][61][62], gastric carcinoma [63], Kaposi's sarcoma and angiosarcoma [64], neuroblastoma [65] and thyroid tumor [66] (see Tab 1). Further, Ang2 expression has been correlated with poor prognosis in NSCLC [67], HCC [62], gastric [63] and breast [68] cancers. In addition, HT29 colon cancer, hepatocellular carcinoma, and MKN-7 gastric cancer cells engineered to overexpress Ang2 demonstrated augmented tumor growth and vessel count compared to vector controls [59,63,69].…”