Bayad Jaza Mahmood

Mechanisms of Lymph Node Metastasis

Unlike benign tumors, malignant tumors can break down natural host barriers and invade the surrounding

host tissue. Tumor invasion and metastasis is an active process, some of the specific molecules involved

in these steps have been studied in many tumor types including HNSCC.

1. Loss of Cell Adhesion:

The overall structure and polarity of epithelial tissues is dependent on tightly regulated cell–cell and cell–

ECM binding. The pattern of attachments is not only important for the integrity of epithelium but also

plays a critical signaling role in cellular orientation, proliferation, and differentiation. In contrast, tumor

cells almost universally exhibit decreased intracellular adhesion. This decrease in adhesion allows cells to

grow outside of the normal limits of epithelial adhesion.

2. Integrins:

Epithelial cells are connected to the basement membrane through the integrin. Integrins are critical

components of hemidesmosomes (prevent cell motility) which anchor cells to the basement membrane

through interaction with laminins 1 and 5 and are therefore found exclusively on the basal surface of

nontumor cells. Overexpression of several of these molecules has been found in immunohistochemical

studies to correlate with metastatic disease in patients with HNSCC.

3. Laminins:

The laminins are a family of glycoproteins, Laminins are components of the basement membrane and

form hemidesmosomes with integrins to control cell adhesion, motility, polarity, and proliferation.

Laminin-5 has been shown to enhance attachment and lamellopodia formation in tumors cells correlating

with increased migration and invasiveness in vitro. HNSCC tumor cells secrete laminin-5 into their

microenvironment.

4. Cadherins:

The cadherins are members of transmembrane glycoproteins that mediate calcium-dependent cell–cell

adhesion. they play important roles in embryogenesis and in the maintenance of normal tissue

architecture. Cadherins are involved in cell recognition, adhesion, and signaling, disruption of cadherin

function has significant implications for the development and behavior of tumors.

5. Focal Adhesion Kinase:

Integrin binding to the ECM activates signaling pathways within the cell. FAK has been discovered to be

an intermediary in this process. Integrin binding leads to activation of FAK which in turn is able to activate

downstream regulators through phosphorylation. Laboratory studies have demonstrated that cells are

able to resist cell death due to loss of adhesion (anoikis) through an FAK-dependent mechanism.

Resistance to anoikis is likely to be a critical step in the survival of cells that break free from the primary

tumor and successfully metastasize to distant sites.

6. Epithelial–Mesenchymal Transition:

The term epithelial-–mesenchymal transition (EMT) has been applied to the process of tumorigenesis

corresponding increase in motility and loss of cell adhesion. Presence of EMT was found to be an indicator

of poor prognosis in patients with HNSCC.

7. Proteolysis and Migration:

Degradation of the ECM is a critical step in tumorigenesis, allowing tumor cells to leave their immediate

environment and conferring the potential for tissue invasion and metastasis.

8. Matrix Metalloproteinases:

MMPs are proteolytic enzymes requiring metal ions as cofactors. MMPs have been shown to have a role

in invasion and metastasis beyond their ability to degrade ECM components. The substrates for MMPs

include non-ECM proteins including growth factors. The activity of MMPs has been shown to release or

activate basic fibroblast growth factor (bFGF), VEGF, and TGF-β, potentially increasing angiogenesis.

9. Urokinase-Type Plasminogen Activator:

The uPA system is believed to play a role in invasion and metastasis. uPA is a protease which is primarily

active in the cleavage of plasminogen to plasmin; activated plasmin can proteolyze a number of

substrates. Increased expression of uPA has been associated with increased invasiveness and metastases.

10. Serpins:

The serpins are tumor suppressors has been demonstrated in a number of tumor types, including HNSCC.

Loss of Serpin expression has been shown to correlate with lymphatic metastasis and decreased disease-

free survival and overall survival in patients with HNSCC.

11. Angiogenesis:

The formation of new blood vessels is critical for the growth, invasion, and metastasis of tumors. Tumors

>1 mm3 require adequate vasculature to avoid necrosis. Not surprisingly, most tumors overcome this

impediment by stimulating endothelial cell proliferation and new blood vessel formation.

Regulators of Angiogenesis

Vascular Endothelial Growth Factor

VEGF is one of the most potent mediators of tumor angiogenesis, inducing endothelial cell proliferation,

migration, and survival and capillary tube formation.

Interleukin-8

Studies on HNSCC cell lines have shown that IL-8 secreted by tumor cells can induce migration and

invasiveness (323) that may relate to the production of MMP-7 in response to IL-8.

Hypoxia

Areas of very low tissue PO2 (<10 mm Hg) are found to exert a potent selective effect on tumor cells and

to have a pronounced effect on tumor invasiveness and metastatic potential.