Tight Junctions in Cancer Metastasis: Unveiling the Gatekeepers of Tumor Progression

Cancer metastasis, the spread of malignant cells from their primary site to distant organs, is a major cause of cancer-related deaths. Metastasis is a complex process involving multiple steps, including the disruption of cell-cell adhesion, invasion through the extracellular matrix, intravasation into the bloodstream, survival in the circulation, extravasation into the target organ, and colonization at the secondary site. Tight junctions (TJs),intercellular junctions that regulate cell polarity, permeability, and adhesion, play a crucial role in the metastatic cascade.

Tight junctions are multi-protein complexes that form the apical most junction between adjacent epithelial and endothelial cells. They are composed of three main protein families: claudins, occludins, and junctional adhesion molecules (JAMs). Claudins and occludins are transmembrane proteins that interact in a homophilic and heterophilic manner to form the backbone of the TJ, while JAMs are single-pass transmembrane proteins that contribute to TJ assembly and function. TJs regulate paracellular permeability by controlling the passage of ions, solutes, and macromolecules through the intercellular space. They also play a role in cell-cell adhesion, cell polarity, and the maintenance of tissue architecture.

Alterations in TJ structure and function are commonly observed in cancer cells, and these changes are associated with increased metastatic potential. Loss of TJ proteins, such as claudins and occludins, has been linked to a decrease in cell-cell adhesion, increased paracellular permeability, and enhanced cell migration and invasion. Conversely, overexpression of certain TJ proteins, such as claudin-4, has been associated with increased tumor growth and metastasis.

Tight Junctions in Cancer Metastasis (Cancer Metastasis - Biology and Treatment Book 19)

by Shane S. Bush

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Language	:	English
File size	:	6120 KB
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The mechanisms underlying TJ disruption in cancer are complex and involve multiple factors, including genetic mutations, epigenetic modifications, and alterations in signaling pathways. Mutations in TJ genes, such as claudin-1, -4, and -7, have been identified in various types of cancer, including breast, lung, and colorectal cancer. These mutations can lead to loss of TJ function, increased paracellular permeability, and enhanced metastatic potential.

Epigenetic modifications, such as DNA methylation and histone deacetylation, can also contribute to TJ disruption in cancer. Aberrant DNA methylation of TJ gene promoters has been associated with decreased expression of TJ proteins and increased cancer cell migration and invasion. Histone deacetylation can also lead to TJ disruption by altering the expression of TJ-associated genes.

Alterations in signaling pathways, such as the Wnt/β-catenin and TGF-β pathways, can also affect TJ function in cancer. Activation of the Wnt/β-catenin pathway has been linked to increased expression of claudins, which can promote cancer cell migration and invasion. Conversely, inhibition of the TGF-β pathway has been shown to decrease claudin expression and reduce cancer cell motility.

The role of TJs in cancer metastasis provides potential therapeutic opportunities. Targeting TJs could inhibit tumor progression and metastasis by restoring cell-cell adhesion, reducing paracellular permeability, and blocking cell migration and invasion. Several strategies are being explored to target TJs for cancer therapy, including:

• Inhibitors of TJ proteins: Small molecule inhibitors and antibodies targeting TJ proteins, such as claudins and occludins, are being developed to disrupt TJ function and inhibit cancer cell migration and invasion.
• Modulators of TJ signaling pathways: Drugs that modulate TJ-associated signaling pathways, such as the Wnt/β-catenin and TGF-β pathways, could restore TJ function and inhibit cancer metastasis.
• Exploiting TJ-specific biomarkers: Identifying TJ-specific biomarkers could help predict metastatic potential and guide therapeutic decisions.

Tight junctions play a critical role in cancer metastasis by regulating cell-cell adhesion, permeability, and polarity. Alterations in TJ structure and function are commonly observed in cancer cells and are associated with increased metastatic potential. Targeting TJs could provide novel therapeutic strategies for inhibiting cancer progression and metastasis.

Tight Junctions in Cancer Metastasis (Cancer Metastasis - Biology and Treatment Book 19)

by Shane S. Bush

5 out of 5

Language	:	English
File size	:	6120 KB
Text-to-Speech	:	Enabled
Screen Reader	:	Supported
Enhanced typesetting	:	Enabled
Print length	:	567 pages

FREE