Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis

Abstract

The effects of breast cancer conventional chemotherapy on tumor angiogenesis need to be further characterized. Neoadjuvant chemotherapy is an ideal model to evaluate the results of chemotherapy, allowing intra-patient direct comparison of antitumor and antiangiogenic effects. We sought to analyze the effect of neoadjuvant chemotherapy on tumor angiogenesis and its clinical significance in breast cancer. Breast cancer patients (n = 108) treated with neoadjuvant sequential anthracyclines and taxanes were studied. Pre- and post-chemotherapy microvessel density (MVD) and mean vessel size (MVS) were analyzed after CD34 immunohistochemistry and correlated with tumor expression of pro- and antiangiogenic factors (VEGFA, THBS1, HIF1A, CTGF, and PDGFA) by qRT-PCR. Angiogenic measures at diagnosis varied among breast cancer subtypes. Pre-treatment higher MVS was associated with triple-negative subtype and more advanced disease. Higher MVS was correlated with higher VEGFA (p = 0.003), while higher MVD was correlated with lower antiangiogenic factors expression (THBS1, p < 0.0001; CTGF, p = 0.001). Increased angiogenesis at diagnosis (high MVS and glomeruloid microvascular proliferation) and higher VEGFA expression were associated with tumor recurrence (p = 0.048 and 0.009, respectively). Chemotherapy-induced angiogenic response (defined as decreased MVD) was present in 35.2 % of patients. This response correlated with an increase in antiangiogenic factors (THBS1) without changes in VEGFA expression, and it was associated with tumor downstaging, but not with clinical response, pathologic complete response, or prognosis. Global effects of chemotherapy mainly consisted in an increased expression of antiangiogenic factors (THBS1, CTGF), with significant changes neither of tumor VEGFA nor of MVS. Conventionally scheduled neoadjuvant chemotherapy exerts antiangiogenic effects, through an increase in antiangiogenic factors, THBS1 and CTGF, but the expression of VEGFA is maintained after treatment. Better markers of angiogenic response and a better understanding of the cooperation of chemotherapy and antiangiogenic therapy in the neoadjuvant clinical scenario are needed.

Angiogenic role of miR-20a in breast cancer

“…Some translational studies suggest that vascular characteristics, related to vessel size and morphology, are associated with prognostic differences in breast cancer. Specifically, a higher vascular size and complexity, experimentally linked to thrombospondin and VEGFA changes, seem to confer a worse prognosis in breast cancer, as others and we have shown before [ 9 , 14 ]. In particular, we have previously characterized a bad-prognosis VEGFA-related angiogenic profile characterized by a higher mean vascular size (MVS) and by the presence of glomeruloid microvascular proliferation (GMP), but without increased microvascular density (MVD).…”

“…Additionally, modulation of tumor angiogenesis by conventional chemotherapy, with potential synergistic and antagonistic effects, further confounds the interpretation of clinical results. In fact, others and we have demonstrated that chemotherapy exerts variable changes in tumor vascular network, which are clearly related neither to pathologic response nor to patients outcome [ 9 – 11 ].…”

Variations of circulating cardiac biomarkers during and after anthracycline-containing chemotherapy in breast cancer patients

“…CRCD does not necessarily imply tissue ischemia [ 18 ] and an increase, rather than a decrease, of miR-126-3p concentrations was found after the chemotherapy. As miR-126-3p is enriched in endothelial cells and promotes blood vessels formation [ 39 ], its upregulation could be a response to cellular stress and anti-angiogenic activity of the chemotherapy [ 40 ]. In the same way, miR-199a-3p levels also decreased in acute heart failure [ 41 ], while our results have shown an elevation after chemotherapy.…”

Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1

“…PDGFA is a well-characterized pro-angiogenic factor in different physiological and pathological conditions including organ development, ischemia and renal diseases [ 34 – 36 ]. In addition, expression of PDGFA has been shown to be associated with high vascular density, lymph node metastasis and tumor recurrence in breast cancer [ 37 , 38 ]. Our data indicated that PDGFA is a direct target of KDM2A and a critical mediator of KDM2A-induced tube formation of endothelial cells (Figure 6 ).…”