Nodal-induced L1CAM/CXCR4 subpopulation sustains tumor growth and metastasis in colorectal cancer derived organoids.
Theranostics
; 11(12): 5686-5699, 2021.
Article
em En
| MEDLINE
| ID: mdl-33897875
ABSTRACT
Background:
Colorectal cancer (CRC) is currently the third leading cause for cancer-related mortality. Cancer stem cells have been implicated in colorectal tumor growth, but their specific role in tumor biology, including metastasis, is still uncertain.Methods:
Increased expression of L1CAM, CXCR4 and NODAL was identified in tumor section of patients with CRC and in patients-derived-organoids (PDOs). The expression of L1CAM, CXCR4 and NODAL was evaluated using quantitative real-time PCR, western blotting, immunofluorescence, immunohistochemistry and flow cytometry. The effects of the L1CAM, CXCR4 and NODAL on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo.Results:
We found that human colorectal cancer tissue contains cancer stem cells defined by L1CAMhigh/CXCR4high expression that is activated by Nodal in hypoxic microenvironment. This L1CAMhigh/CXCR4high population is tumorigenic, highly resistant to standard chemotherapy, and determines the metastatic phenotype of the individual tumor. Depletion of the L1CAMhigh/CXCR4high population drastically reduces the tumorigenic potential and the metastatic phenotype of colorectal tumors.Conclusion:
In conclusion, we demonstrated that a subpopulation of migrating L1CAMhigh/CXCR4high is essential for tumor progression. Together, these findings suggest that strategies aimed at modulating the Nodal signaling could have important clinical applications to inhibit colorectal cancer-derived metastasis.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Organoides
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Receptores CXCR4
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Molécula L1 de Adesão de Célula Nervosa
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Proliferação de Células
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Proteína Nodal
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Metástase Neoplásica
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article