Cytokines chattering in pancreatic ductal adenocarcinoma tumor microenvironment

Rakesh Bhatia, Namita Bhyravbhatla, Andrew Kisling, Xiaoqi Li, Surinder K. Batra, Sushil Kumar

Research output: Contribution to journalReview articlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) consists of multiple cell types interspersed by dense fibrous stroma. These cells communicate through low molecular weight signaling molecules called cytokines. The cytokines, through their receptors, facilitate PDAC initiation, progression, metastasis, and distant colonization of malignant cells. These signaling mediators secreted from tumor-associated macrophages, and cancer-associated fibroblasts in conjunction with oncogenic Kras mutation initiate acinar to ductal metaplasia (ADM), resulting in the appearance of early preneoplastic lesions. Further, M1- and M2-polarized macrophages provide proinflammatory conditions and promote deposition of extracellular matrix, whereas myofibroblasts and T-lymphocytes, such as Th17 and T-regulatory cells, create a fibroinflammatory and immunosuppressive environment with a significantly reduced cytotoxic T-cell population. During PDAC progression, cytokines regulate the expression of various oncogenic regulators such as NFκB, c-myc, growth factor receptors, and mucins resulting in the formation of high-grade PanIN lesions, epithelial to mesenchymal transition, invasion, and extravasation of malignant cells, and metastasis. During metastasis, PDAC cells colonize at the premetastatic niche created in the liver, and lung, an organotropic function primarily executed by cytokines in circulation or loaded in the exosomes from the primary tumor cells. The indispensable contribution of these cytokines at every stage of PDAC tumorigenesis makes them exciting candidates in combination with immune-, chemo- and targeted radiation therapy.

Original languageEnglish (US)
JournalSeminars in Cancer Biology
DOIs
StateAccepted/In press - 2022

Keywords

  • Cytokines
  • immunotherapy
  • metastasis
  • Pancreatic ductal adenocarcinoma
  • tumor microenvironment

ASJC Scopus subject areas

  • Cancer Research

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