Acquisition of anoikis resistance promotes the emergence of oncogenic K-ras mutations in colorectal cancer cells and stimulates their tumorigenicity in vivo

Mathieu Derouet, Xue Wu, Linda May, Hoon Yoo Byong, Takehiko Sasazuki, Senji Shirasawa, Janusz Rak, Kirill V. Rosen

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Detachment from the extracellular matrix causes apoptosis of normal epithelial cells - a phenomenon called anoikis. K-ras oncogene, an established anoikis inhibitor, often occurs in colorectal carcinoma (CRC). In addition to blocking anoikis-inducing mechanisms, oncogenic K-ras can cause anoikis-unrelated changes in CRC cells, such as induction of events promoting their deregulated mitogenesis, ability to trigger angiogenesis, and so on. Thus, whether ras-induced anoikis resistance of CRC cells is essential for their ability to form tumors in vivo or represents a mere epiphenomenon is unclear. We found that when poorly tumorigenic, oncogenic, K-ras-negative, anoikis-susceptible human CRC cells were cultured under anoikis-inducing conditions in vitro, they spontaneously gave rise to an anoikis-resistant cell population harboring de novo oncogenic K-ras mutations and manifesting dramatically increased tumorigenicity. We further observed that a variant of the same oncogenic K-ras-negative anoikis-susceptible cells selected for increased tumorigenicity acquired de novo oncogenic K-ras mutations and manifested increased anoikis resistance. Unlike the case with anoikis, oncogenic K-ras did not rescue CRC cells from death caused by hypoxia or anticancer agents. Taken collectively, our results support the notion that ras-induced anoikis resistance of CRC cells is essential for their ability to form tumors in vivo and thus represents a potential therapeutic target.

Original languageEnglish
Pages (from-to)536-545
Number of pages10
JournalNeoplasia
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cancer Research

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