In Vivo Studies

To validate the hypothesis that surgically derived cytokines accelerate metastasis of colon carcinomas, in vivo experiments were carried out. These experiments were carried out in different tumor systems: human tumors in nude mice, murine or rat tumors in syngeneic mice or rats, respectively, and tumors that formed metastases to liver, lung, or intraperitoneal dissemination.

Injection of the proinflammatory cytokines TNF-a or IL-1P before tumor cell injection in experimental animals promoted formation of metastases. This effect was also found when animals received surgical stress instead of proinflam-matory cytokines prior to tumor cell injection. In these animals serum levels of proinflammatory cytokines were elevated after surgery. Administering antibodies against the cytokines inhibited the enhanced metastasis after surgery. For example, we performed a study in which rats underwent a hemihepatectomy, ileum resection, or sham operation after injection of CC531 rat colon carcinoma cells. After 3 weeks, the animals were killed. Tumor recurrence in the lung was significantly higher in hemihepatectomy and ileum resection groups compared to sham groups, indicating that surgical trauma influences the metastasis process. Studies comparing laparotomy versus laparoscopy show the relation between the degree of surgical trauma and metastasis, since less tumor recurrence was found after laparoscopy than after laparotomy.

From these in vivo studies we can conclude that surgery-derived cytokines play a major role in tumor recurrence. However, cytokine pretreatment did not induce metastasis by tumor cell lines that were not metastatic, nor did it change their metastatic homing, indicating that cytokines quantitatively modulate the metastasis process without changing the intrinsic metastatic properties of tumor cells.

Because tumor cell adhesion to the endothelium seems to be an important step in metastasis, experimental studies have been performed to investigate the role of endothelial adhesion molecules in enhanced metastasis. In these studies, antibodies against adhesion molecules on tumor cells or on endothelial cells were administered to animals prior to surgery and indeed inhibited the enhanced metastasis.

Another mechanism of enhanced tumor recurrence after surgery may be the accelerated growth of tumor cells under the influence of surgery-derived mediators, such as cytokines and growth factors. However, several studies contradict the hypothesis that enhanced growth of tumor cells is responsible for accelerated metastasis formation after surgery. Therefore, acceleration of metastasis appeared to be independent of the effect of the cytokine on the primary tumor growth.

These in vivo studies demonstrate a relation between surgery and accelerated metastasis via the release of proin-flammatory cytokines. These cytokines induce adhesion molecules on the vascular endothelium, causing increased tumor cell adhesion.

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