Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

Abstract

KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I–IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging.

Body mass index, C-reactive protein, and pancreatic cancer: A Mendelian randomization analysis to investigate causal pathways

“…Hence, inflammatory factors are of great significance for the occurrence, development, prognosis, and survival of PC. In addition to CRP, interleukin-18, TPX3, interleukin (IL)-33, etc., have potential for further exploration as well ( 12 , 33 , 34 ).…”

Insights into the Relationship between Pentraxin-3 and Cancer

“…Candidate biomarkers for early diagnosis in pancreatic cancers are crucial to be found as this type of cancer is frequently recognized too late [ 120 , 121 ]. PTX-3 is secreted and expressed in case of pancreatic cancer by pancreatic stellate cells (believed to be the precursors of carcinoma) [ 122 , 123 , 124 , 125 ].…”

“…Kamal et al detected high levels of PTX-3 in early stages of pancreatic adenocarcinoma for 200 patients and also obtained good sensitivity and specificity values (0.63 and 0.85, respectively) for PTX-3 in proteomics analysis, suggesting therefore the quantification of serum PTX-3 as a reliable diagnostic biomarker [ 120 ]. Consistent with these results, Goulart et al found a better predictive value (97%) for PTX-3 overexpression in diagnosing pancreatic cancer, with higher sensitivity and specificity (0.86 and 0.86) for values above 4.34 ng/mL [ 122 ].…”

“…Consistent with these results, Goulart et al found a better predictive value (97%) for PTX-3 overexpression in diagnosing pancreatic cancer, with higher sensitivity and specificity (0.86 and 0.86) for values above 4.34 ng/mL [ 122 ]. However, in comparison with other types of cancer, PTX-3 serum levels were not different among patients with long or short survival rates [ 120 ]. Therefore, Goulart et al proposed PTX-3 as a reliable stromal-derived diagnostic biomarker in patients with pancreatic ductal adenocarcinoma [ 122 ].…”

Pancreatic Cancer: From Genetic Mechanisms to Translational Challenges

“…In the search for early detection biomarkers for PDAC, Kamal MA et al reported on KRAS-induced secreted proteins, identifying high levels of LAMC2 and PTX3 detected at the early stages (I–IIB) and PDAC patients with low levels of in CA19-9 patients. They suggest that LAMC2 and PTX3 released via systemic circulation may be helpful in selecting patients for future diagnostic imaging [ 8 ].…”