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Study of breast cancer adaptation to anti-­angiogenic therapies by molecular imaging on tissue slides

Publication Date
  • Angiogenesis
  • Maldi Imaging
  • Cancer
  • Human Health Sciences :: Multidisciplinary
  • General & Others [D99]
  • Sciences De La Santé Humaine :: Multidisciplinaire
  • Généralités & Autres [D99]
  • Biology
  • Geography
  • Medicine


Breast carcinoma is the most common and second leading cause of cancer mortality in women1. The ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣␣␣ ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣ ␣␣␣␣-­‐limiting secondary step in tumorigenesis led to extensive pre-­‐clinical researches on angiogenesis and finally the approval of VEGF-­‐neutralizing antibodies (bevacizumab) and VEGF receptor tyrosine kinase inhibitors (RTKs:sunitinib). The Sunitinib has been used clinically in patients with breast cancer refractory to other therapeutic agents2. Unfortunately, like the cytotoxic therapies, these drugs do not produce lasting effects and resistance to treatment appeared clinically3. Recently, independent laboratories have reported experimental data demonstrating that anti-­‐ angiogenic treatments inhibit tumor growth, but also stimulate the formation of lung metastases after treatment discontinuation4. The field of imaging mass spectrometry provides new tools to visualize and study the profiles of proteins and small molecules associated with biomedical problems5. To this aim, we conducted a series of experiments to setup a reproductible model of resistance to sunitinib. The cells MDA-­‐MB-­‐231 triple negative, from human breast cancer and expressing luciferase are injected subcutaneously into mice RAG1-­‐/-­‐. The mice were divided into four experimental groups including, on the one hand, control mice treated with placebo (Carboxymethyl cellulose, CMC) sacrificed on day 30 (group 1) or when the tumor reached a volume of 300 mm3 (group 2). On the other hand, Sunitinib-­‐treated mice (LC Laboratories, 40mg/kg/day), sacrificed at day 30 (group 3), or when the tumor reached a volume of 300 mm3 (group 4). MALDI mass spectrometry imaging was performed on tissue sections of tumors and organs subsequently colonized by metastases. Matrix sublimation was used to coat tumor sections (14 μm-­‐tick) with 1.5 Diaminonaphthalene (1.5 DAN) for lipids analysis and Sinapinic acid (SA) for entire proteins analysis. Ion cartographies were recorded with a Solarix9.4T FTMS instrument for lipids and with an Ultraflex II TOF-­‐TOF instrument for entire proteins (BrukerDaltonics, Bremen, Germany) with a spatial resolution of 100 μm. The analysis of differential protein/lipid profiles with high mass accuracy and broadband resolution allows detection of intense signals from lipid families such as Phosphatidylcholine (PC), Triglyceride (TAG), Sphingomyelin (SM) and precise lipid droplets or tumor cells differentiated location in the Sunitinib resistant tumor cells compared to control cells.The protein profiles of the 4 groups of mice show differences in intensity and location, enabling a correlation to inflammatory (highlighted by histological staining) and angiogenic phenomenon.

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