Abstract
BackgroundThe tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival.MethodsPancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon resection. Homogenates were subjected to multiplex analysis of 41 inflammatory mediators.ResultsTwenty-three mediators were significantly elevated in adenocarcinoma specimens compared to nonmalignant controls. Increased intratumoral IL-8 concentrations associated with larger tumors (P = .045) and poor differentiation (P = .038); the administration of neoadjuvant chemotherapy associated with reduced IL-8 concentrations (P = .003). Neoadjuvant therapy was also associated with elevated concentrations of Flt-3 L (P = .005). Elevated levels of pro-inflammatory cytokines IL-1β (P = .017) and TNFα (P = .033) were associated with a poor histopathologic response to neoadjuvant therapy. Elevated concentrations of G-CSF (P = .016) and PDGF-AA (P = .012) correlated with reduced overall survival. Conversely, elevated concentrations of FGF-2 (P = .038), TNFα (P = .031) and MIP-1α (P = .036) were associated with prolonged survival.ConclusionThe pancreatic cancer microenvironment harbors a unique inflammatory milieu with potential diagnostic and prognostic value.
Highlights
The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis
We examined the inflammatory milieu present in the PC microenvironment from 36 freshly resected tumor specimens using a forty-one-item panel of cytokines, chemokines and growth factors to test the hypothesis that expression levels of these mediators harbor diagnostic and prognostic value
Pancreatic adenocarcinoma has a distinct intratumoral inflammatory milieu Establishing the diagnosis of PC remains a significant clinical problem that delays initiation of therapy, impacts enrollment in clinical trials, and mandates that patients undergo major surgical procedures in the absence of definitive findings
Summary
The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. Inflammation within the PC microenvironment has been mechanistically linked to tumor progression and chemoresistance through NF-κB, IL-6, toll-like receptor and TGF-β signaling pathways [6,7,8,9,10]. While survival gains from immune cell infiltration into the tumor microenvironment have been conclusively demonstrated in colorectal and ovarian cancer [11,12,13], similar investigations have not yielded consistent results in PC [14, 15]. Patients with chronic pancreatitis are 5–15 times more likely to develop PC [16] and insights into the association between inflammation and PC stems from investigations of chronic pancreatitis. The translational relevance of the microenvironmental inflammatory milieu to PC development and progression remains speculative
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