Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers

Abstract

BackgroundCancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (α-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and α-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort.MethodsTumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and α-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients.ResultsHigh expression of FAP-1, but not α-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40–0.99) was significantly associated with increased disease-specific survival. FAP-1 and α-SMA were not significantly correlated to each other. Analyses of FAP-1 and α-SMA associated with other tumor-related proteins revealed histotype-specific correlation patterns.ConclusionThe presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype.

Clinical significance of FAP-α on microvessel and lymphatic vessel density in lung squamous cell carcinoma

“…Liao et al observed that high FAP-α is associated with poor prognosis in NSCLC 6. In another cohort, Kilvaer et al found that FAP-α indicates a better patient outcome in predicting disease free survival in lung squamous cell carcinoma and adenocarcinoma 7. Our study clearly demonstrated a prognostic value of CAF density in predicting survival for lung squamous cell carcinoma, one of the most frequent subtypes of NSCLC.…”

“…It was recently demonstrated that FAP-α could serve as a novel predictor for survival6 in patients with NSCLC, with high FAP-α being a marker for poor survival. Subsequently, another study investigated the role of FAP-α in squamous cell carcinoma and adenocarcinoma in lung7 and found that increased abundance of this marker protein correlates with increased disease-free survival (DFS). Hence, this contradiction in disease outcome needs further analyses.…”

Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer

“…However, the prognostic value of standard markers of activated TAFs had remained ill defined in NSCLC. Thus, the prognostic value of α-SMA had remained unclear due to conflicting observations [13,14], whereas that of fibrillar collagens has not been assessed directly.…”

“…In contrast, little is known on the clinical relevance of standard markers of activated fibroblasts in histologic samples from NSCLC patients. Thus very few studies have examined the prognostic value of stromal alpha-smooth muscle actin (α-SMA) in lung cancer, which is the gold standard marker of fibroblast activation [12]; moreover these studies have reported contradictory results [13,14], underscoring that the prognostic value of α-SMA in NSCLC remains unclear. In addition to α-SMA, the deposition of fibrillar (type I and III) collagens is another common marker of activated fibroblasts; however, to our knowledge their prognostic value in NSCLC has not been determined.…”

Role of Alpha-Smooth Muscle Actin and Fibroblast Activation Protein Alpha in Ovarian Neoplasms

“…Its isolated expression does not express fibroblasts associated with cancer. Therefore, other fibroblast markers should be used, such as vimentin, fibronectin, and the FAP used in our study, which according to some authors is considered the main marker of fibroblasts [23]. …”