Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery

Abstract

Purpose To evaluate the relevance between lumican expression patterns and the clinical course of PDAC patients, and to investigate the role of lumican in PDAC progression. Experimental Design 131 patient tumors were chosen for tissue microarray staining and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and HIF-1α and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Results Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and three-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF-1α expression and activity via Akt. PDAC cells with enhanced HIF-1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. Conclusions There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.

Transforming Growth Factor-β Limits Secretion of Lumican by Activated Stellate Cells within Primary Pancreatic Adenocarcinoma Tumors

“…Using the Kaplan-Meier method, the median survival of the stromal lumican high group (≥DAB mean) was 16.05 months compared to 10.2 months for the stromal lumican low patient group (<DAB mean) (Figure 1d). This trend is consistent with our previous observations (19) although the difference did not reach statistically significance (p=0.32) due to the small sample size. The clinicopathologic characteristics in the patient groups with high or low stromal lumican expression was also compared and is displayed in Supplementary Table 2.…”

“…In previous work, we identified that cancer-related survival in pancreatic cancer patients is associated with the amount and distribution of lumican within the primary PDAC tumor (19). In this study we performed IHC staining of a unique cohort of PDAC tumor specimens and observed the presence of lumican within both cancer cells as well as the stroma (Figure 1a).…”

“…Its complex and diverse proteoglycan structure suggests that lumican influences cell function through a variety of mechanisms (17, 18). We have previously demonstrated that the presence of lumican in the ECM surrounding, but not within, PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC (19). The cell source and the molecular mechanisms controlling the secretion of lumican into the ECM of PDAC and other solid tumors are currently unknown.…”

Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma

“…Thirty to fifty micrograms of protein was used for western blotting analysis. Detailed methods can be found in our previous publication (26). …”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…The study showed that patients who had PG localized mostly in the stromal rather than the epithelial area also presented a decrease in metastatic recurrence. In vivo model showed that lumican decreased EGFR (epidermal growth factor receptor) and HIF-1α expression via Akt; cancer cells with enhanced HIF-1α activity became resistant to lumican-induced inhibition of glucose consumption and apoptosis [180]. Therefore, lumican acts against pancreatic cancer cell development, protecting the microenvironment from the consequences of HIF-1α, and is correlated with tumor progression.…”