PD08-07: Wound-Healing Drainage Fluids Promote Triple Negative Breast Cancer Progression.
Authors: M Campiglio, M Sasso, F Bianchi, I Plantamura, M Iorio, L De Cecco, E Giustarini, R Agresti, C Ghirelli, M Cremona, C Tripodo, E Tagliabue
Journal: Cancer Research (2011)

Abstract Triple negative breast cancers (TNBC) account for 15% of breast cancers. TNBCs carry a high risk of recurrence and deaths, due to the high rate of local and systemic relapse in these patients and no therapeutic options except chemotherapy are currently available. The TNBC pattern of recurrence present a distant recurrence peak at approximately 3 years and then declines rapidly thereafter, whereas in all non-TNBC types the recurrence risk seems to be constant over time. TNBC relapse risk is comparable to that of HER2−positive tumors subtype, in which growth-factors released during the healing process accelerate the early recurrences in HER2−positive patients. Thus, we speculate that also TNBC early relapse may depend on their capability to respond to wound-healing stimulation. To this aim, TNBC were treated with drainages to identify which receptors/pathways can be activated and play a driving role in TNBC progression. A pilot reverse phase protein microarray (RPMA) experiment on MDA-MB-231 TN cells drainage-fluids stimulated revealed a specific activation of PDGFR and VEGFR and their downstream pathways, whereas no significant changes were observed in other receptors, such as EGFR, IRS, Met and ERB3. The type of activated receptors suggested the involvement of endothelial receptors upon drainages stimulation and, indeed TNBC cell lines expressed endothelial molecules, such as CD34, CD31, CD146. Beside the proved role of some of these receptors in cellular proliferation, the TNBC endothelial-like phenotype prompt us to analyzed TNBC cell lines capability to form vascular-like channels when seeded on matrigel. Drainages were able to accelerate the formation of vascular channels in TNBC cell lines and, moreover to consistently increase proliferation of TNBC cells compared to non-TNBC cells. To prove whether receptors found activated by drainages play a key role in TNBC progression, we targeted PDGFR, VEGFR and other receptors possibly involved in angiogenesis and vasculogenic mimicry with sunitinib (targeting PDGFR, VEGFR, FGF and c-kit), anti-bFGF antibody (Ab)(targeting the ligand bFGF) and bevacizumab (targeting the VEGF) in TNBC cells drainage-stimulated in vitro. Sunitinib and anti-bFGF Ab halved the proliferation of TNBC cell lines and reduced of almost 60% the formation of vascular-like channels in TNBC cells, whereas bevacizumab modestly affect proliferation but not vasculogenic properties. Notably, sunitinib and anti-bFGF Ab strongly inhibited MDA-MB-231 and MDA-MB-468 xenografts tumor growth (sunitinib: 80%, and 70% Growth Index (GI), respectively; anti-bFGF Ab 70% and 60% GI, respectively) whereas bevacizumab determined no more than 30% decrease of tumor volume. Unfortunately, all these drugs did not efficiently control the development of lung metastases, that indeed significant increased compared to their control, possibly through induction of hypoxia processes. In conclusion, wound healing promotes TNBC progression by sustaining proliferation and vasculogenesis. The use of sunitinib and anti-bFGF antibody strongly inhibited tumor growth in mice models, but significantly increased lung metastases suggesting a combined use of these drugs with molecules able to interfere with hypoxia pathway. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-07.