Journal
MOLECULAR NUTRITION & FOOD RESEARCH
Volume 66, Issue 15, Pages -Publisher
WILEY
DOI: 10.1002/mnfr.202200248
Keywords
chemoprevention; colon cancer; M2-like TAMs; metastasis; piceatannol; TGF-beta 1
Categories
Funding
- Ministry of Science and Technology [109-2320-B-002-012-MY3, 110-2320-B-002-019-MY3]
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This study identified a specific molecular mechanism that can prevent the progression and metastasis of colorectal cancer by regulating the interaction between tumor-associated macrophages and cancer cells. The results showed that piceatannol (PIC) effectively inhibited the aggressive features and stemness of cancer cells by restricting the polarization of M2-like macrophages and blocking the positive feedback loop of transforming growth factor beta 1 (TGF-beta 1) in the tumor microenvironment. In vivo experiments also demonstrated significant repression of tumor growth and lung metastases with the administration of PIC.
Scope: M2 phenotype tumor-associated macrophages (M2-TAMs) play a key role in distant metastasis and poor clinical outcomes. Herein, a specific molecular mechanism that contributes to malignant progression is illuminated and investigates whether piceatannol (PIC) can target the crosstalk between M2-TAMs and cancer cells for potential colorectal cancer (CRC) therapy. Methods and results: To mimic the tumor microenvironment (TME), direct and indirect coculture systems in vitro and in vivo mouse xenograft models are established. The results demonstrate that post-treatment with PIC in TME more effectively prevented the aggressive features and stemness of SW480 cells by restricting the polarization of M2-like macrophages and blocking the transforming growth factor beta 1 (TGF-beta 1) positive feedback autocrine/paracrine loop that exists between M2-like polarized macrophages and cancer cells. Furthermore, xenograft assays also observe significant repression in tumor growth and lung metastases with the administration of PIC. The key mechanism underlying the antimetastasis effects of PIC may include its directly inhibitory activity against TGF-beta receptor type-1 (TGF-beta R1) in the M2-like TAMs-created TME. Conclusion: These novel findings demonstrate that PIC is a potent TGF-beta 1/TGF-beta R1 pathway inhibitor and TME modulator for preventing tumor progression and metastasis in CRC by reeducating TAMs.
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