Overexpression of focal adhesion kinase correlates with increased lymph node metastasis and poor prognosis in non-small-cell lung cancer

Park

Clinical Cancer Research

et al. 2013

121

Purpose: Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the a-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas.Experimental Design: ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2.Results: The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics.Conclusions: These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma.

Section: Discussionmentioning

confidence: 99%

Alpha-Smooth Muscle Actin (ACTA2) Is Required for Metastatic Potential of Human Lung Adenocarcinoma

Park

Clinical Cancer Research

et al. 2013

121

Journal of Thoracic Oncology

“…12 Another study demonstrated correlation between FAK overexpression and more advanced stages of disease using 153 NSCLC frozen tissues in Chinese patients. 10 The authors reported that FAK overexpression was associated with lymph node metastasis and more advanced stages of NSCLC. FAK overexpression was independently associated with worse overall survival, suggesting it as a significant prognostic factor in addition to pathologic stage.…”

Section: Discussionmentioning

confidence: 99%

“…7–9 FAK has been shown to be overexpressed in colon tumors compared to normal matched samples by both immunohistochemistry and RT-PCR. 6 Recently, FAK was found to be overexpressed in lung tumors, and its higher expression correlated with nodal spread and advanced disease stages, 10–12 suggesting its important role in lung cancer progression and metastasis. Moreover, activation of FAK, along with SRC, promote cell migration and adhesion in LKB1-deficient KRAS mutant lung tumors, a genotype associated with high propensity for nodal and distant metastases.…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Significance of Focal Adhesion Kinase Expression in Stage I Non–Small-Cell Lung Cancer

Ylagan

Pokharel

et al. 2014

INTRODUCTION Focal Adhesion Kinase (FAK) plays a significant role in cancer cell survival signaling and is overexpressed in various malignancies, including lung cancer. Previous studies suggest that FAK overexpression is an independent factor predicting poor prognosis in NSCLC. The aim of this study is to confirm these findings specifically in stage I NSCLC. MATERIALS AND METHODS A retrospective tissue microarray (TMA) analysis of FAK protein expression by immunohistochemistry (IHC) was performed in 157 surgically resected stage I NSCLC specimen and in the corresponding matched normal lung tissue. The FAK 4.47 monoclonal antibody was used for FAK immunostaining. The scoring system of triplicate tumor cores included intensity of staining plus extent of staining for a composite score that ranged from 0–6. The association between FAK score and survival was evaluated. RESULTS There were 103 stage IA and 54 stage IB patients, with mean follow-up of 5.5 years. Normal lung alveoli and interstitial tissue had mean FAK score of 0 (median score 0, range 0–2). Tumor samples had mean FAK score 3.1 (median score 3.5, range 0–6), with 57% of the samples having FAK score ≥ 3. Continuous FAK score was not associated with demographic data, tumor histology or grade, nor survival in this cohort of stage I NSCLC patients. CONCLUSIONS FAK is expressed in more than 50% of stage I NSCLC lung cancer but not in normal lung alveoli and interstitial tissue. FAK expression is not associated with survival outcome in this North American cohort.

“…Results from our clinical cohort suggest that ovarian cancer is similar to other solid tumours, including breast and lung, in which increased transcript copy numbers of FAK and paxillin are linked to poor prognosis [23][24][25][26][27][28]. Our clinical cohort isolated those groups of patients who had poorly differentiated tumours, and those patients who died from the disease and/or had associated incidence.…”

Section: Discussionmentioning

confidence: 98%

The clinical and biological implications of the focal adhesion kinase pathway in ShenLingLan mediated suppression of cellular migration of ovarian cancer cells

Owen¹,

Ruge²,

Yang³

et al. 2017

J Cancer Res Ther.

The incidence of ovarian cancer in the UK has increased by almost twenty percent since the 1970's and the majority of cases are not diagnosed until the late stages, when metastasis is more likely to have occurred. Focal Adhesion Kinase (FAK) is one of the key protein complexes which is integral to cell migration and has been linked to a variety of solid tumours. ShenLingLan (SLDM) is a traditional herbal medicine which has been formulated for the treatment of solid tumours. This study aimed to establish the impact of SLDM on FAK in ovarian cancer cells in vitro and transcript levels of FAK in an ovarian cancer cohort. FAK and paxillin phosphorylation events stimulated by SLDM treatment were identified using a Kinexus TM antibody based protein array. The impact of SLDM on cell attachment and migration was evaluated using Electric cell-substrate impedance sensing (ECIS), whilst the changes in focal adhesion complex localisation were assessed using immunofluorescence. In an ovarian cancer cohort, differences in FAK and paxillin transcript levels were assessed against key clinical parameters such as differentiation, stage and survival outcome. SLDM treatment of ovarian cancer cells in vitro resulted in the suppression of FAK and paxillin phosphorylation at several sites, which appeared to manifest as decreased cellular attachment and migration in a range of immortalised ovarian cancer cells. Increased FAK and paxillin transcript copies were observed in high grade and poorly differentiated ovarian tumours as well as in tumours from patients with ovarian cancer related incidence. SLDM has a profound effect on the migratory and adhesive properties of ovarian cancer cells, potentially via inhibitory effects on the activation of the FAK pathway, which is aberrant in clinical ovarian cancers.