Acquisition of Anoikis Resistance Promotes the Emergence of Oncogenic K-ras Mutations in Colorectal Cancer Cells and Stimulates Their Tumorigenicity In Vivo

Neoplasia: An International Journal for Oncology Research

Senji Shirasawa¹  Takehiko Sasazuki²  Janusz Rake³  Kirill V. Rosen⁴  Mathieu Derouet⁴  Xue Wu⁴  Byong Hoon Yoo⁴  Linda May⁵ 

[1] Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan;Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan;Department of Pediatrics, McGill University Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada;Departments of Pediatrics and Biochemistry and Molecular Biology, Atlantic Research Center, Dalhousie University, Halifax, Nova Scotia, Canada;Henderson Research Center, McMaster University, Hamilton, Ontario, Canada;

关键词: Colorectal cancer;    ras;    anoikis;    apoptosis;    extracellular matrix;   

DOI  :  10.1593/neo.07217

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown