PT  - JOURNAL ARTICLE
AU  - Carter, Julia H.
AU  - Douglass, Larry E.
AU  - Deddens, James A.
AU  - Colligan, Bruce M.
AU  - Bhatt, Tejal R.
AU  - Pemberton, Jackson O.
AU  - Konicek, Susan
AU  - Hom, Joanne
AU  - Marshall, Mark
AU  - Graff, Jeremy R.
TI  - Pak-1 Expression Increases with Progression of Colorectal Carcinomas to Metastasis
AID  - 10.1158/1078-0432.CCR-03-0210
DP  - 2004 May 15
TA  - Clinical Cancer Research
PG  - 3448--3456
VI  - 10
IP  - 10
4099  - http://clincancerres.aacrjournals.org/content/10/10/3448.short
4100  - http://clincancerres.aacrjournals.org/content/10/10/3448.full
SO  - Clin Cancer Res2004 May 15; 10
AB  - Purpose: The p21-activated kinase-1 (Pak-1) promotes cell motility and invasiveness. Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3′-kinase/AKT pathway activation. Because Pak-1 plays a central role in regulating cell motility and invasiveness, we sought to determine whether Pak-1 may be involved in the malignant progression of colorectal carcinoma. Experimental Design: Pak-1 expression was examined by immunohistochemistry in archived tissues from normal human colons, tubular and tubulovillous adenomas, invasive adenocarcinomas (stages I-III/IV), and lymph node metastases (184 total specimens from 38 patients). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore (stain intensity × percentage of epithelium stained). Results: Pak-1 expression was increased significantly with colorectal cancer progression from normal tissue to lymph node metastases (P < 0.0001). Furthermore, Pak-1 expression was increased significantly in adenomas, invasive carcinomas, and lymph node metastases compared with normal colon (P < 0.0001). Strikingly, Pak-1 expression was significantly higher in lymph node metastases than in invasive cancers, adenomas, or normal colon (P < 0.0001). Moreover, in patients with multiple lesions representing different stages of disease, Pak-1 expression was increased specifically in the most advanced lesions. Conclusions: This study demonstrates that Pak-1 expression is increased significantly with malignant progression of human colorectal carcinoma. These data, along with numerous functional studies demonstrating a central role for Pak-1 activity in tumor invasiveness and motility, implicate Pak-1 as an exciting target for therapy of colorectal carcinoma.