Table 1.

Involvement of TLRs in inducing susceptibility and resistance to different human cancers.

Cancer(s)	Mode of involvement of TLRs	Associated TLRs	Pathological consequences and contributing factors	References
Brain and Neural cancer	Activation of NF-κB signaling and modulation of p38/MAPK pathway causing cell growth and viability; induce overexpression of membrane type 1 matrix-bound metalloproteinase (MT1-MMP) in microglia activating tumor-released MMP2 leading to metastasis	TLR2	Increased expression in glioma biopsies; decrease patient survival; promote tumor growth	(60–62)
	Promotion of tumor growth mediated via the inflammatory signaling pathways	TLR4	Higher protein expression in U118, U87, A172, and LN229 glioma cell lines, regulation of cell survival, immune infiltration, and tumor progression	(62)
	Trigger TLR9-MYD88 signaling in a STAT3-dependent way	TLR9	Glioma stem cell (GSC) formation	(67)
Head and neck cancer	Expressed over the keratinocytes in oral squamous cell carcinoma	TLR2	Overexpressed significantly across the primary tumors, regulate apoptosis of tumor cells	(72)
	The mutated genotype of TLR3 is associated with the development of carcinoma	TLR3	Overexpressed in head neck and oral squamous cell carcinoma; poor survival	(73)
	Induction of signaling cascade mediated via MyD88 inducing secretion of inflammatory cytokine, chemokines, and epithelial to mesenchyme transition	TLR4	Higher expression, tumor differentiation and proliferation, poor survival, and disease severity	(71, 74)
	Promotion of tumor growth mediated via the induction of inflammatory signaling pathways	TLR5, 7, 9	TLR5 expression is associated with a lower grade of tongue cancer; TLR7 is upregulated in oral carcinoma showing poor differentiation and prognosis; TLR9 shows higher expression in primary oral cell carcinoma but lower across squamous cell carcinoma	(71, 75, 76)
Esophageal cancer	Expressed in esophageal squamous cell carcinoma mediated through the activation of NF-κB	TLR3, 4, 7, and 9	overexpressed in esophageal squamous cell carcinoma; TLR3, 4, and 9 associated with lymph node metastasis; TLR7 and 9 expressions related to poor histological grade; TLR4 stimulation by LPS increases migration and adhesive properties	(79)
	Stimulation of TLR4 with LPS resulted in NF-κB activation and increased IL-8 secretion	TLR1, 2, 4 and 6	Overexpressed in EAC; TLR9 expression is associated with metastasis, poor grade of differentiation, and prognosis	(78)
Lung cancer	Epigenetic regulation and transcriptional activation. Production of anti-inflammatory cytokines	TLR2, 3	Promotes tumor growth and proliferation	(84)
	Activation by LPS stimulation leads to activation of the PI3K/AKT signaling pathway. Production of anti-inflammatory cytokines. Extracellular matrix remodeling and EGFR-mediated signaling	TLR4	increase in the proliferation of human lung adenocarcinoma cell line A549; upregulating anti-apoptotic protein Bcl-2 and downregulating pro-apoptotic protein; increased metastasis	(37)
	Activation of the NF-κB signaling pathway. Upregulation of anti-apoptotic protein Bcl-2	TLR7, 8	Increase in tumor cell survival and chemoresistance	(90)
Breast cancer	Promote tumor growth mediated via the inflammatory signaling pathways. Activation of the MyD88/NF-κB and AKT pathways. Release of TLR2-activating DAMPs, such as HMGB1	TLR2	TLR2 shows ten-fold lower expression in malignant MDA-MB-231 cells; TLR2 promotes the survival, invasion of these cancer cells, and induction of chemoresistance	(101–104)
	Induction of strong TRIF-dependent production of IFN-β, together with NF-κB activation. Activation of Wnt/β-catenin and NF-κB signaling pathways	TLR3	Release of pro-apoptotic cytokines and activation of caspases. For example, activation of caspase-1 from procaspase-1 is induced by IL-1β. Increase of metastasis and promotion of the CSC phenotype and mammosphere-like structure	(102, 107)
	LPS triggered increased expression of TLR4 downstream MyD88 signaling cascade to felicitate inflammatory responses	TLR4	Overexpressed, increased cell proliferation, lymph node metastasis; regulate expression of integrin αvβ3-mediated adhesion and invasiveness of metastatic breast cancer cells	(108)
	Induction of inflammatory responses through binding of TLR agonist(s)	TLR5, 9	Overexpressed breast cancerous cells promote cancer progression and poor survival	(109)
Pancreatic cancer	TLR2 binds with HMGB1 and activate PI3K/Akt as well as Wnt/β-catenin pathways for generating tumor-promoting milieu	TLR2	Overexpression; poor progression of disease; increased metastasis	(112)
	Activation of NF-κB and modulation of gene expression such as MMP2,9 in response to stimulation by LPS, leading to the expansion of the tumor cells	TLR4	Upregulation of TLR4 resulted in cancer proliferation, increased angiogenesis, metastasis, and disease progression and severity	(114)
	Stimulation by viral ssRNA and/or ligand leads to immune activation and proliferation	TLR7, 8	Increased in the progression from PanINs to metastatic cancer; downregulation of cell cycle regulators including cyclin D1, p16, PTEN and the upregulation of p27, p53, p21, cyclin B1, PPARγ, and TGF-β; resistant to chemotherapy	(113, 114)
Hepatocellular cancer	Nuclear translocation and activation of VEGF and Caspase-3 genes	TLR2	Upregulation of TLR2 increased cell proliferation and expression of vascularization markers	(121)
	Induction of stem-like features via activation of the TLR4/Nanog pathway	TLR4	Upregulation of TLR4 increased microvascular invasion	(126)
	Activation of NF-κB pathway as well as p-Akt expression	TLR7 and TLR9	Upregulation od TLR7 and TLR9 increased HCC cell proliferation	(129)
Gastric cancer	Interact with Helicobacter pylori and mediate the production of proinflammatory cytokines and chemokines	TLR3, 4, 5, 9	Interact with H. pylori to induce gastric carcinoma, overexpressed; increase dysplasia and metaplasia; lymph node metastasis, poor prognosis, and poor survival	(149, 150)
Colorectal carcinoma	Formation of heterodimers with TLR1 and/or TLR6 to initiate the signaling cascade for activating the transcription factors like NF-κB and AP-1	TLR2	Increased tumor formation and increased levels of IL-6, IL-17A, and STAT3; show antitumor activities	(93, 94)
	TLR4 is activated by bacterial LPS and lipoteichoic Acid (LTA). Upon recognition by LPS Binding Protein (LBP), it transfers to the differentiation-14 (CD14) receptor or MD-2, which are the accessory proteins involved in the ligand recognition, dimerization, and endocytosis of TLR4	TLR4	Activation of NF-κB through the MYD88 pathway, leading to transcription of pro-inflammatory cytokines as well as induction of Nox-derived ROS, resulting in tumor cell metastasis	(190, 191)
	TLR9 is located in the cytoplasm and intracellular endosomes recognize unmethylated CpG motifs in bacterial DNA	TLR9	Involved in colitis−associated colorectal carcinogenesis by regulating NF−κB expression levels	(192, 193)
Ovarian cancer	Binds to dsRNA and analogs to initiate a signaling cascade by activating NF-κB leading to the upregulation of IFN-α and IFN-β, CTL, and NK cells	TLR3	Overexpression and tumor progression promote cancer cell growth and survival; elevated production of cytokines (IL-6) and chemokines	(184, 188)
	Over the tumor cells, the LPS stimulates the TLR4 for the increased production of IL-6, inhibiting CTLs for cancer cell detection and death	TLR4	Overexpression in cancerous epithelial cells; immunosuppression; increased cancer cell survivability and tumor progression; development of chemoresistance to Paclitaxel	(185, 187, 189)
	Hypomethylated tumor DNA released from the tumor cells binds to TLR9 to trigger the signaling cascade promoting tumorigenesis	TLR9	Increased expression leads to disease severity, poor survival, increased tumor grade, and metastasis	(34, 186)
Hematologic Cancers	SNPs rs3804100 (S450S) and rs4696480 (16933T>A)	TLR2	Associated with marginal zone lymphoma (MZL), increases the risk of follicular lymphoma (FL), and decreases the risk of chronic lymphocytic leukemia (CLL). Its expression is also associated with poor prognosis in CLL patients	(194–196)
	SNP rs4986790 (A299G)	TLR4	linked with an elevated risk for MALT lymphoma. It could trigger a cascade resulting in Mantle cell lymphoma (MCL) growth and evasion from the immune system	(195, 197)
	SNPs rs5743836 (1237T>C) and rs352140 (2848 G/A)	TLR9	Associated with an elevated risk for NHL and linked with lack of cell death in the Mutu-I and BJAB Burkitt lymphoma (BL) cell lines. It could be a potential biological marker for the response to BL treatment	(198, 199)