Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1.
Metastasis of primary tumors leads to a very poor prognosis for patients suffering from cancer. Although it is well established that not every tumor will eventually metastasize, it is less clear whether primary tumors acquire genetic alterations in a stochastic process at a late stage, which make them invasive, or whether genetic alterations acquired early in the process of tumor development drive primary tumor growth and determine whether this tumor is going to be metastatic. To address this issue, we tested genes identified in a large-scale comparative genomic hybridization analysis of primary tumor for their ability to confer metastatic properties on a cancer cell. We identified amplification of the ACK1 gene in primary tumors, which correlates with poor prognosis. We further show that overexpression of Ack1 in cancer cell lines can increase the invasive phenotype of these cells both in vitro and in vivo and leads to increased mortality in a mouse model of metastasis. Biochemical studies show that Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac. Taken together, this study supports a theory from Bernards and Weinberg [Bernards, R. & Weinberg, R. A. (2002) Nature 418, 823], which postulates that the tendency to metastasize is largely predetermined.
van der Horst
Edward Htun
EH
Department of Biology, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Degenhardt
Yan Y
YY
Strelow
Astrid
A
Slavin
Anthony
A
Chinn
Lawrence
L
Orf
Jessica
J
Rong
Minqing
M
Li
Shyun
S
See
Lei-Hoon
LH
Nguyen
Ken Q C
KQ
Hoey
Timothy
T
Wesche
Holger
H
Powers
Scott
S
D000818:Animals; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D050719:Crk-Associated Substrate Protein; D039201:Integrin alpha3beta1; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D020744:rac GTP-Binding Proteins