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Modulating the Distant Spreading of Patient-Derived Colorectal Cancer Cells via Aspirin and Metformin.

Translational oncology (2020-04-05)
Gemma Palazzolo, Hilaria Mollica, Valeria Lusi, Mariangela Rutigliani, Martina Di Francesco, Rui Cruz Pereira, Marco Filauro, Laura Paleari, Andrea DeCensi, Paolo Decuzzi
ABSTRACT

Although screening has reduced mortality rates for colorectal cancer (CRC), about 20% of patients still carry metastases at diagnosis. Postsurgery chemotherapy is toxic and induces drug resistance. Promising alternative strategies rely on repurposing drugs such as aspirin (ASA) and metformin (MET). Here, tumor spheroids were generated in suspension by primary CRCs and metastatic lymph nodes from 11 patients. These spheroids presented a heterogeneous cell population including a small core of CD133+/ESA+ cancer stem cells surrounded by a thick corona of CDX2+/CK20+ CRC cells, thus maintaining the molecular hallmarks of the tumor source. Spheroids were exposed to ASA and/or MET at different doses for up to 7 days to assess cell growth, migration, and adhesion in three-dimensional assays. While ASA at 5 mM was always sufficient to mitigate cell migration, the response to MET was patient specific. Only in MET-sensitive spheroids, the 5 mM ASA/MET combination showed an effect. Interestingly, CRCs from diabetic patients daily pretreated with MET gave a very low spheroid yield due to reduced cancer cell survival. This study highlights the potential of ASA/MET treatments to modulate CRC spreading.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Heparin sodium salt from porcine intestinal mucosa, Grade I-A, ≥180 USP units/mg, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
D-(+)-Glucose, powder, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99.5%
Supelco
Metformin hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Aspirin, meets USP testing specifications
Sigma-Aldrich
Progesterone, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Putrescine dihydrochloride, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Anti-Active-β-Catenin (Anti-ABC) Antibody, clone 8E7, clone 8E7, Upstate®, from mouse
Nunc® Lab-Tek® Chamber Slide system, 8 wells, Permanox® slide, 0.8 cm2/well, sterile, 96/cs