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The promise of CD44v6, a therapeutic target for colon cancer
Author(s) -
Misra Suniti,
Hascall Vincent C.,
Markwald Roger R.,
Ghatak Shibnath
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.967.3
Subject(s) - hepatocyte growth factor , cancer research , carcinogenesis , angiogenesis , colorectal cancer , clonogenic assay , pi3k/akt/mtor pathway , medicine , signal transduction , receptor , cancer , chemistry , cell , biology , microbiology and biotechnology , biochemistry
Objective The proposed study links CD44v6 and its cross‐talk with growth factor receptor signaling pathways in colon tumorigenesis, and the use of colon tumor specific delivery of CD44v6shRNA through nanoparticles will suppress tumorigenesis. Methods Mechanism of sustained production of CD44v6 in response to stimulation of hepatocyte growth factor (HGF) were studied in non metastatic primary intestinal epithelial cell line Apc10.1 isolated from Apc Min/+ mice. Involvement of CD44v6 in clonogenic growth, sphere formation, motility and in vitro angiogenesis were studied in human colon rectal cancer (CRC) cell lines. CD44v6shRNA through nanoparticles were delivered intraperitonially to immunodeficient mice carrying HT29 xenograft and the effect of CD44v6shRNA on tumorigenesis and CD44v6 signaling were studied. Results Mechanistically, CD44v6 acts as co‐receptor for c‐Met and VEGFR2 were observed. HGF effect on CD44v6 is inducible whereas CCD44v6 physically binds with VEGFR2 for its activation. CD44v6 forms a positive feed‐back loop with PI3K for sustained production of CD44v6. CD44v6shRNA reduces xenograft growth by 80–90% within ten treatments. Conclusion The data provide new insights into growth factor induced CD44v6 splicing mechanism and its role in CRC and suggest that CD44v6shRNA/nanoparticles delivery is a promising strategy for targeting CRC tumor growth and progression.