Discussion

The studies just mentioned give compelling evidence that interactions between tumor cells and the endothelium play a pivotal role in metastasis formation to distant sites, involving a multiplicity of adhesion molecule complexes. These adhesive interactions are susceptible to regulation by proinflammatory cytokines, which are capable of causing tumor cell arrest in the microvasculature and strongly influence the outcome of the metastatic process.

Comparing the results obtained with macrovascular cells with those obtained with microvascular cells, there are discrepancies. According to Paget's "seed and soil" hypothesis, certain tumor cells have their preferential organs to metasta-size to, which cannot be explained by simple anatomical or mechanical hypotheses. Each organ microenvironment has different characteristics, such as a different pattern of endothelial adhesion molecules, reacting in particular ways to stimuli. This can explain typical metastasis patterns for specific tumors. Therefore, it is a prerequisite to study endothelial cells derived from the vascular bed of interest rather than extrapolate from results obtained with HUVECs.

Most studies are performed under static conditions. However, the metastatic process is a dynamic one. Tumor cells circulating in the vasculature encounter shear forces that are associated with the blood flow. These shear forces may prevent tumor cell and endothelial cell interactions that could occur under static conditions. The studies mentioned earlier use culture systems lacking shear forces. Nevertheless, useful data have been acquired with static assays, providing evidence that adhesive interactions are susceptible to regulation by environmental stimuli such as cytokines. Furthermore, tumor cell endothelial cell interactions take place in the microvasculature where the role of shear forces is limited, since blood flow in the microvasculature is low.

Dynamics are not only related to blood flow. The inflammatory response is a dynamic process involving a whole range of mediators. Those mediators can affect each other, resulting in a complicated network. Stimulation of endothelial cells with proinflammatory cytokines not only bring about the induction of adhesion molecules; endothelial cells are also triggered to release mediators themselves. The production of endothelial proinflammatory cytokines therefore will enhance the inflammatory state, leading to a vicious circle. Not only endothelial cells can produce proinflammatory cytokines; tumor cells can as well. Research regarding the issue whether tumor cells produce enough cytokines to stimulate endothelial cells is contradictory. Some reports claim that tumor cell-derived cytokines indeed stimulate endo-thelial cells, resulting in increased tumor cell adhesion, whereas others could not detect such a stimulative effect.

Other mediators are released during the inflammatory response and tissue injury, such as reactive oxygen species, chemokines, prostaglandins, and growth factors. Moreover, circulating cells, such as monocytes, neutrophils, platelets, and erythrocytes, may prevent or support tumor cell-endothelial cell interactions. All these factors produce dynamic interactions that may influence the metastasis process.

The apparent relationship between the inflammatory response after surgical trauma and distant tumor recurrence necessitates further unraveling of the mechanisms involved. This may bring about a treatment modality to reduce distant recurrences and benefit a significant proportion of patients in terms of survival or quality of life.

Glossary

Cell adhesion molecule: Although this could mean any molecule involved in cellular adhesive phenomena, it has acquired a more restricted sense, namely a molecule on the surface of animal tissue cells, antibodies against which specifically inhibit some form of intercellular adhesion.

Colon cancer: Disease in which malignant (cancer) cells are found in the tissues of the colon.

Microvascular endothelium: Comprises of a layer of thin flattened cells lining the inside surfaces of small blood vessels, like arterioles, venules and capillaries.

Proinflammatory cytokines: Primarily produced by white blood cells (monocytes and macrophages); has an antineoplastic effect but causes inflammation.

References

1. Sugarbaker, E. V. (1981). Patterns of metastasis in human malignancies. Cancer Biol. Rev. 2, 235-278.

2. Lee, K. H., Lawley, T. J., Xu, Y. L., and Swerlick, R. A. (1992). VCAM-1-, ELAM-1-, and ICAM-1-independent adhesion of melanoma cells to cultured human dermal microvascular endothelial cells. J. Invest. Dermatol. 98(1), 79-85.

3. Pauli, B. U., Augustin-Voss, H. G., el-Sabban, M. E., Johnson, R. C., and Hammer, D. A. (1990). Organ-preference of metastasis. The role of endothelial cell adhesion molecules. Cancer Metastasis Rev. 9(3), 175-189.

Further Reading

Aosasa, S., Ono, S., Mochizuki, H., Tsujimoto, H., Osada, S., Takayama, E., Seki, S., and Hiraide, H. (2000). Activation of monocytes and endothelial cells depends on the severity of surgical stress. World. J. Surg. 24, 10-16.

Auerbach, R., Alby, L., Morrissey, L. W., Tu, M., and Joseph, J. (1985). Expression of organ-specific antigens on capillary endothelial cells.

Microvasc. Res. 29, 401-411. Auerbach et al. showed that capillary endothelial cells express an array of antigens on their cell surface that manifest organ selectivity. Chambers, A. F., Groom, A. C., and MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews 2, 563-572.

Giavazzi, R. (1986). Cytokine-mediated tumor-endothelial cell interaction in metastasis. Curr. Top. Microbiol. Immunol. 213(Pt 2), 13-30. This review gives an excellent overview of the current knowledge about tumor cell—endothelial cell interactions in metastasis under influence of cytokines.

Haier, J., and Nicolson, G. L. (2001). The role of tumor cell adhesion as an important factor in formation of distant colorectal metastasis. Dis. Colon Rectum 44, 876-884. Haier and Nicolson summarized and dis cussed different aspects of colorectal carcinoma cell adhesion during hematogenous formation of distant metastases.

Orr, F. W., and Wang, H. H. (2001). Tumor cell interactions with the microvasculature. A rate-limiting step in metastasis. Surg. Oncol. Clin. North Am. 10, 357—381. This comprehensive review describes the vascular phase of cancer metastasis.

Weiss, L. (1990). Metastatic inefficiency. Adv. Cancer Res. 54, 159-211.

Capsule Biography

As a Ph.D. researcher, M. ten Kate, M.D., is investigating tumor cell endothelial interactions under influence of surgical trauma. This research is carried out under supervision of C. H. J. van Eijck, M.D., Ph.D., an oncologic surgeon at the Erasmus Medical Center in Rotterdam.

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