Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers

Wu, Chun; Kang, Yew Beng; Pichika, Mallikarjuna Rao

doi:10.2147/ott.s50838

Cited by 65 publications

(57 citation statements)

References 165 publications

(202 reference statements)

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“…Recently, enhanced expression of TLRs has been described in a variety of different tumor entities and depending on the cancer type, could be linked to either favorable or poor prognosis [7,8,9,10,11]. TLR3 and -4 were identified as predictors of poor survival in breast cancer, whereas high TLR9 predicted enhanced survival [12,13].…”

Section: Introductionmentioning

confidence: 99%

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Grimmig

Moench

Kreckel

et al. 2016

IJMS

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Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Grimmig

Moench

Kreckel

et al. 2016

IJMS

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“…T regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells mediate local immune inhibitory environment (2,19); which may decrease anti-tumor immunity, or promote cancer cell transformation (4,20). Thus, immune inhibitory cytokines and chemokines and decreased anti-tumor immunities in the local microenvironment may promote PCa cell survival, activation, proliferation, invasion, and metastasis (20). Further studies need to investigate the role of bacterial translocation in altering systemic inflammation, antitumor immunities, and PCa biology.…”

Section: Discussionmentioning

confidence: 99%

Increased Preoperative Plasma Level of Microbial 16S rDNA Translocation Is Associated With Relapse After Prostatectomy in Prostate Cancer Patients

Zhou

Turner

et al. 2020

Front. Oncol.

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Background: The environmental factors for promoting prostate cancer (PCa) recurrence remain unknown. Methods: A retrospective cross-sectional study was conducted in healthy men (n = 12) and PCa patients undergoing prostatectomy (n = 27). Plasma preoperative level of total cell-free bacterial 16S rDNA, a marker of microbial translocation, was evaluated by qPCR. Plasma levels of prostate-specific antigen (PSA) were evaluated by ELISA. Results: Similar degrees of microbial translocation were found in healthy men and patients. However, the levels of microbial 16S rDNA were increased in patients with cancer relapse (n = 10) compared to patients without relapse (n = 17) after prostatectomy. Furthermore, the levels of microbial 16S rDNA were marginally increased in patients with pT3 or pT4 tumors compared to those with pT 2 or less. The levels of microbial 16S rDNA tended to increase in patients with higher pathologic tumor stage, Gleason score, and margin and lymph node involvements; but these differences did not reach significance. Conclusion: The plasma 16S rDNA levels increased in patients with PCa who have biochemical recurrence and 16S rDNA levels were higher in patients with higher-grade PCa.

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“…A better known mechanism of omega-3 fatty acid action applies to their pro-apoptotic and anti-inflammatory activity on tumor cells (e.g., regulation of Bcl-2, Bax and c-Myc, and effects on lipids metabolism) [161–163]. Tissue samples derived from patients with head and neck, esophageal, gastric, colorectal, liver, pancreatic, skin, breast, ovarian, cervical, and breast cancer were shown to express increased amounts of TLR4 [164], indicating that modulation of the TLR4 signaling pathway would have a beneficial effect on most common cancers.…”

Section: Innate Antibacterial Signalingmentioning

confidence: 99%

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

Słotwiński

Słotwińska

2016

cejoi

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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.

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Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers

Cited by 65 publications

References 165 publications

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

Increased Preoperative Plasma Level of Microbial 16S rDNA Translocation Is Associated With Relapse After Prostatectomy in Prostate Cancer Patients

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

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