Pak-1 expression increases with progression of colorectal carcinomas to metastasis.
OBJECTIVE
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.


METHODS
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 x 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.
Carter
Julia H
JH
Wood Hudson Cancer Research Laboratory, Newport, Kentucky 41071, USA. jcarter@woodhudson.org
Douglass
Larry E
LE
Deddens
James A
JA
Colligan
Bruce M
BM
Bhatt
Tejal R
TR
Pemberton
Jackson O
JO
Konicek
Susan
S
Hom
Joanne
J
Marshall
Mark
M
Graff
Jeremy R
JR
D000236:Adenoma / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D016896:Treatment Outcome; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D018631:ras Proteins / Q000378:metabolism
D020558:GTP Phosphohydrolases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D018631:ras Proteins; C515903:PAK1 protein, human