Stromal Expression of Heat-Shock Protein 27 Is Associated with Worse Clinical Outcome in Patients with Colorectal Cancer Lung Metastases

Pulmonary metastases are common in patients with primary colorectal cancer (CRC). Heat- shock protein 27 (Hsp27) is upregulated in activated fibroblasts during wound healing and systemically elevated in various diseases. Cancer-associated fibroblasts (CAFs) are also thought to play a role as prognostic and predictive markers in various malignancies includ- ing CRC. Surprisingly, the expression of Hsp27 has never been assessed in CAFs. There- fore we aimed to investigate the expression level of Hsp27 in CAFs and its clinical implications in patients with CRC lung metastases

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer

Krebs von den Lungen 6 (KL-6) is a Novel Diagnostic and Prognostic Biomarker in Pleural Mesothelioma

International audienceObjectives: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM.Materials and methods: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro.Results: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort.Conclusion: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM

Kaplan-Meier plots showing the lung-metastasis free survival, recurrence free survival and overall survival after metastasectomy dependent on stromal Hsp27 (A), stromal α-SMA (B) and tumor Hsp27 (C) scoring.

<p>Kaplan-Meier plots showing the lung-metastasis free survival, recurrence free survival and overall survival after metastasectomy dependent on stromal Hsp27 (A), stromal α-SMA (B) and tumor Hsp27 (C) scoring.</p

The degree of Hsp27 expression score in the tumor stroma correlated significantly with the expression of stromal α-SMA (A).

<p>CD31-positive microvessels surrounded by tumor stroma next to tumor cells (asterisk) (B). MVD was significantly increased in primary tumors and metastases with strong stromal Hsp27 expression (C). Immunofluorescence showed a co-expression of stromal Hsp27 and α-SMA especially in PM (400x magnification) (D).</p

Total Hsp27 (A), phospho-Hsp27 (B) and IL-8 (C) were measured in serum samples of healthy volunteers, patients with CRC lung metastases before and 3 months after metastasectomy (each n = 10; whiskers indicate standard deviation).

<p>Total Hsp27 (A), phospho-Hsp27 (B) and IL-8 (C) were measured in serum samples of healthy volunteers, patients with CRC lung metastases before and 3 months after metastasectomy (each n = 10; whiskers indicate standard deviation).</p