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The role of toll-like receptors in colorectal cancer progression: evidence for epithelial to leucocytic transition.

Luddy KA, Robertson-Tessi M, Tafreshi NK, Soliman H, Morse DL - Front Immunol (2014)

Bottom Line: In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines.Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression.Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Imaging and Metabolism, Imaging and Technology Center of Excellence, H. Lee Moffitt Cancer Center , Tampa, FL , USA.

ABSTRACT
Toll-like receptors (TLRs) are expressed by immune cells, intestinal epithelium, and tumor cells. In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines. Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression. Activation of these TLRs can induce inflammation, tumor cell proliferation, immune evasion, local invasion, and distant metastasis. These TLR-influenced behaviors have similarities with properties observed in leukocytes, suggesting that tumors may be hijacking immune programs to become more aggressive. The concept of epithelial to leucocytic-transition (ELT) is proposed, akin to epithelial to mesenchymal transition, in which tumors develop the ability to activate leucocytic traits otherwise inaccessible to epithelial cells. Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.

No MeSH data available.


Related in: MedlinePlus

Epithelial to leucocytic transition (ELT) is the acquisition of immune properties by tumor cells. Epithelial tumor cells (purple box) can make transition to a mesenchymal phenotype (orange box), which enhances local motility and remodeling of the extracellular matrix (ECM). Tumor cells undergoing ELT (green box) can gain the ability to (1) evade the immune system at the primary tumor site, (2) access the lymphatic system, (3) circulate through the vasculature, home to favorable sites of metastasis, and extravasate into a metastatic niche, and (4) avoid destruction by the immune system at the site of metastasis.
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Figure 1: Epithelial to leucocytic transition (ELT) is the acquisition of immune properties by tumor cells. Epithelial tumor cells (purple box) can make transition to a mesenchymal phenotype (orange box), which enhances local motility and remodeling of the extracellular matrix (ECM). Tumor cells undergoing ELT (green box) can gain the ability to (1) evade the immune system at the primary tumor site, (2) access the lymphatic system, (3) circulate through the vasculature, home to favorable sites of metastasis, and extravasate into a metastatic niche, and (4) avoid destruction by the immune system at the site of metastasis.

Mentions: Pathogenic EMT has its roots in normal embryogenesis. In cancer, this transition results in epithelial cells with a range of mesenchymal protein expression. These alterations increase motility and invasive capability of tumor cells, but do not necessarily explain immunoevasion, lymphatic access, and metastatic spread (35, 69, 72). We therefore propose the parallel concept of epithelial to leucocytic transition (ELT) as a framework, akin to EMT, with which to understand the metastatic properties of cancer cells. Figure 1 illustrates the primary properties gained by tumor cells that undergo ELT. We consider ELT to be a partial transition in which epithelial cells retain their epithelial origin while at the same time acquiring a set of leucocytic traits. Tumor cells co-opt many mechanisms of the immune system for their own transport and these mechanisms are activated by proteins typically reserved for the immune response. A leucocytic tumor cell expresses proteins that allow for regulation and co-opting of the immune system such as PD-L1, CD80/86, TLR, TGF-β, CCL4, and CCL5 (80) (Figure 1, properties 1 and 4). Additional leucocytic proteins (CXCR4, CCR7, CCR8) facilitate invasion and proliferation within lymph nodes (Figure 1, property 2) (35, 42, 81). Processes critical to survival in circulation, homing to tissue specific sites, and successful extravasation are mediated by E/P-selectins, L-selectin ligands, α4β1, ICAM-1, and VCAM-1 (61, 73, 82–86) (Figure 1, property 3). By harnessing mechanisms usually reserved for immune cells, tumor cells gain the ability to become more aggressive. In the case of TLRs, a cycle of overexpression and resulting inflammation promotes plasticity of the epithelial phenotype. This plasticity permits tumor cells to undergo ELT, accessing immune programs that facilitate invasion and metastasis of the cancer. ELT, as with other plastic states, is likely transient, making the evaluation of these phenotypes a significant challenge. TLR-mediated evolution of CRC may be a good model to study how ELT occurs, since TLRs are primarily seen in immune cells and the overexpression of TLRs appears to promote an immune-like phenotype in CRC.


The role of toll-like receptors in colorectal cancer progression: evidence for epithelial to leucocytic transition.

Luddy KA, Robertson-Tessi M, Tafreshi NK, Soliman H, Morse DL - Front Immunol (2014)

Epithelial to leucocytic transition (ELT) is the acquisition of immune properties by tumor cells. Epithelial tumor cells (purple box) can make transition to a mesenchymal phenotype (orange box), which enhances local motility and remodeling of the extracellular matrix (ECM). Tumor cells undergoing ELT (green box) can gain the ability to (1) evade the immune system at the primary tumor site, (2) access the lymphatic system, (3) circulate through the vasculature, home to favorable sites of metastasis, and extravasate into a metastatic niche, and (4) avoid destruction by the immune system at the site of metastasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202790&req=5

Figure 1: Epithelial to leucocytic transition (ELT) is the acquisition of immune properties by tumor cells. Epithelial tumor cells (purple box) can make transition to a mesenchymal phenotype (orange box), which enhances local motility and remodeling of the extracellular matrix (ECM). Tumor cells undergoing ELT (green box) can gain the ability to (1) evade the immune system at the primary tumor site, (2) access the lymphatic system, (3) circulate through the vasculature, home to favorable sites of metastasis, and extravasate into a metastatic niche, and (4) avoid destruction by the immune system at the site of metastasis.
Mentions: Pathogenic EMT has its roots in normal embryogenesis. In cancer, this transition results in epithelial cells with a range of mesenchymal protein expression. These alterations increase motility and invasive capability of tumor cells, but do not necessarily explain immunoevasion, lymphatic access, and metastatic spread (35, 69, 72). We therefore propose the parallel concept of epithelial to leucocytic transition (ELT) as a framework, akin to EMT, with which to understand the metastatic properties of cancer cells. Figure 1 illustrates the primary properties gained by tumor cells that undergo ELT. We consider ELT to be a partial transition in which epithelial cells retain their epithelial origin while at the same time acquiring a set of leucocytic traits. Tumor cells co-opt many mechanisms of the immune system for their own transport and these mechanisms are activated by proteins typically reserved for the immune response. A leucocytic tumor cell expresses proteins that allow for regulation and co-opting of the immune system such as PD-L1, CD80/86, TLR, TGF-β, CCL4, and CCL5 (80) (Figure 1, properties 1 and 4). Additional leucocytic proteins (CXCR4, CCR7, CCR8) facilitate invasion and proliferation within lymph nodes (Figure 1, property 2) (35, 42, 81). Processes critical to survival in circulation, homing to tissue specific sites, and successful extravasation are mediated by E/P-selectins, L-selectin ligands, α4β1, ICAM-1, and VCAM-1 (61, 73, 82–86) (Figure 1, property 3). By harnessing mechanisms usually reserved for immune cells, tumor cells gain the ability to become more aggressive. In the case of TLRs, a cycle of overexpression and resulting inflammation promotes plasticity of the epithelial phenotype. This plasticity permits tumor cells to undergo ELT, accessing immune programs that facilitate invasion and metastasis of the cancer. ELT, as with other plastic states, is likely transient, making the evaluation of these phenotypes a significant challenge. TLR-mediated evolution of CRC may be a good model to study how ELT occurs, since TLRs are primarily seen in immune cells and the overexpression of TLRs appears to promote an immune-like phenotype in CRC.

Bottom Line: In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines.Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression.Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Imaging and Metabolism, Imaging and Technology Center of Excellence, H. Lee Moffitt Cancer Center , Tampa, FL , USA.

ABSTRACT
Toll-like receptors (TLRs) are expressed by immune cells, intestinal epithelium, and tumor cells. In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines. Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression. Activation of these TLRs can induce inflammation, tumor cell proliferation, immune evasion, local invasion, and distant metastasis. These TLR-influenced behaviors have similarities with properties observed in leukocytes, suggesting that tumors may be hijacking immune programs to become more aggressive. The concept of epithelial to leucocytic-transition (ELT) is proposed, akin to epithelial to mesenchymal transition, in which tumors develop the ability to activate leucocytic traits otherwise inaccessible to epithelial cells. Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.

No MeSH data available.


Related in: MedlinePlus