Adhesion Molecules

Because of the observed time dependence in tumor-endothelial cell interactions, a role of protein synthesis leading to the induction or upregulation of adhesion molecules is suggested in the enhanced tumor cell adhesion.

In vitro studies using HUVECs revealed the importance of the adhesion molecules ICAM-1, VCAM-1, and E-selectin in tumor cell-endothelial cell interactions. For gastrointestinal carcinomas such as colon, gastric, and pancreas carcinoma, E-selectin seems to be the major adhesion molecule in cytokine-stimulated endothelial interactions.

For HUVECs it is known that under the influence of proinflammatory cytokines, adhesion molecules are inducted or upregulated. In resting conditions HUVECs lack E-selectin and VCAM-1 expression. By proinflammatory cytokines such as TNF-a, E-selectin is rapidly synthesized and expressed on HUVECs after 4 hours of stimulation, with peak values between 4 and 6 hours. VCAM-1 expression reaches peak values after 6 to 12 hours of stimulation, and expression declines thereafter. ICAM-1 is constitutively expressed on HUVECs but is upregulated by TNF-a after 8 hours, remaining high for approximately 24 hours.

Only a few reports regarding the influence of cytokines on adhesion molecule expression on microvascular endothe-lium are available.

On HMVEC-L, E-selectin is rapidly expressed after TNF-a and IL-1b stimulation, with peak expression after 8 hours, followed by a decline (Figure 3). ICAM-1 expression slowly increases, with enhancement still present 24 hours after starting stimulation with TNF-a and IL-1p. The same kinetics, but less pronounced, is observed for VCAM-1 expression. IL-6 does not increase E-selectin expression or ICAM-1 or VCAM-1 expression. Both E-selectin and ICAM-1 expression are correlated with cytokine concentration; the expression increases with increasing concentration.

Adhesion molecule expression in relation to cytokine stimulation is also described for human intestinal, dermal, and CNS microvascular endothelial cells. These studies show induction of the adhesion molecules ICAM-1, VCAM-1, and E-selectin largely similar to HUVECs, although there are discrepancies in time and extent of expression. Other studies show the existence of organ specific adhesion molecules. For example, the group of Pauli [3] reported a new lung-specific adhesion molecule that mediated lung metastasis of murine melanomas.

The influence of proinflammatory cytokines on the expression of adhesion molecules on tumor cells is described only in few reports. These reports found only minor changes that were not impressive enough to cover the enhancement in tumor cell endothelial cell interactions under influence of cytokines.

The kinetics of E-selectin expression on HMVEC-L are conflicting with the adhesion assays, because maximal E-selectin expression is seen after 8 hours of stimulation, whereas maximal adhesion of colon and pancreas carcinoma cells occurs after 12 hours of stimulation. These results exclude E-selectin as the principal adhesion molecule responsible for the enhanced adhesion. And since adhesion of both colon and pancreas carcinoma cells to HMVEC-L was not inhibitable by an E-selectin antibody, it is more

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Figure 3 Kinetics of adhesion molecule expression on HMVEC-L assessed by EIA. HMVEC-L monolayers were pre-incubated with TNF-a or IL-1 b for varying times. Data represent mean absorbance values (OD 405 nm) ± SD.

likely that another adhesion molecule or complex of adhesion molecules is responsible for the enhanced adhesion.

Essentials of Human Physiology

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