Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer

Abstract

Disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer. Multi-regulatory properties of the Toll-like receptors (TLRs) (e.g., regulation of proliferation, the activity of NF-κB, gene transcription of apoptosis proteins, regulation of angiogenesis, HIF-1α protein expression) are used in experimental studies to better understand the pathogenesis of pancreatic cancer, for early diagnosis, and for more effective therapeutic intervention. There are known numerous examples of TLR agonists (e.g., TLR2/5 ligands, TLR6, TLR9) of antitumor effect. The direction of these studies is promising, but a small number of them does not allow for an accurate assessment of the impact of TLR expression disorders, proteins of these signaling pathways, or attempts to block or stimulate them, on the results of treatment of pancreatic cancer patients. It is known, however, that the expression disorders of proteins of innate antibacterial response signaling pathways occur not only in tumor tissue but also in peripheral blood leukocytes of pancreatic cancer patients (e.g., increased expression of TLR4, NOD1, TRAF6), which is one of the most important factors facilitating further tumor development. This review mainly focuses on the genetic aspects of signaling pathway disorders associated with innate antibacterial response in the pathogenesis and diagnosis of pancreatic cancer.

Genetic Alterations of TRAF Proteins in Human Cancers

“…Although beyond the scope of this review, we would like to point out that as critical regulators of adaptive immunity, innate immunity, and inflammation ( 1 – 4 ), TRAF proteins may indirectly contribute to the development, progression, and metastasis of various cancers by affecting tumor surveillance, tumor immunity, chronic inflammation and the tumor microenvironment. For example, disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer, and increased expression of TRAF6, TLR4, and NOD1 are detected in peripheral blood leukocytes of pancreatic cancer patients ( 337 ). Specific deletion of TRAF3 from myeloid cells leads to development of B lymphomas and liver cancer in mice ( 56 , 174 ).…”

Toll-like receptor 6 inhibits colorectal cancer progression by suppressing NF-κB signaling

“…Reportedly, the activation of TLR2 and TLR6 receptors by synthetic lipopeptide significantly reduces tumor growth in mice [ 37 ]. Moreover, intratumoral injection of a toll-like receptor 2/6 agonist has been reported to reduce pancreatic tumor proliferation and metastasis [ 12 , 38 ]. The present study revealed that TLR6 exerted a protective role in the pathogenesis and progression of colon cancer.…”

“…Reportedly, TLRs are expressed in various normal epithelial and cancer cells. Moreover, previous studies have shown that TLRs are widely implicated in gut inflammation in colitis-associated cancers, as well as in the development of CRC [ [10] , [11] , [12] ].…”