Experimentally induced liver metastases from colorectal cancer can be prevented by mononuclear phagocyte-mediated monoclonal antibody therapy

• Published in: Journal of hepatology Vol. 53; no. 4; pp. 677 - 685
• Main Authors: van der Bij, Gerben J, Bögels, Marijn, Otten, Marielle A, Oosterling, Steven J, Kuppen, Peter J, Meijer, Sybren, Beelen, Robert H.J, van Egmond, Marjolein
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01-10-2010; Elsevier
• Subjects: ADCC; Animals; Antibodies, Monoclonal - therapeutic use; Antibody therapy; Biological and medical sciences; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Combined Modality Therapy; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Kupffer cell; Leukocytes, Mononuclear; Liver Neoplasms - drug therapy; Liver Neoplasms - prevention & control; Liver Neoplasms - secondary; Liver Neoplasms - surgery; Liver Neoplasms, Experimental; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophage; Medical sciences; Metastasis; Mice; Phagocytes; Phagocytosis; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Surgery; Treatment Outcome; Tumors; antibody dependent phagocytosis; Metastasis; natural killer; Surgery; KC; fetal calf serum; Antibody therapy; ADCC; colorectal cancer; intraperitoneal; immunoglobulin; ADPh; Fc gamma receptor; i.p; mAb; Kupffer cell; antibody dependent cellular cytotoxicity; CRC; FCS; monoclonal antibody; FcγR; NK; Ig; Phagocytosis; Macrophage; Colorectal cancer; Rectal disease; Hepatic disease; Malignant tumor; Monoclonal antibody; Colonic disease; Prevention; Liver cancer; Treatment; Gastroenterology; Digestive diseases; Intestinal disease; Liver metastasis; Cancer
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.04.023

Background & Aims Development of liver metastases is a frequent complication in patients with colorectal cancer (CRC), even after successful resection of the primary tumor. As such, post-operative adjuvant therapies that aim to eliminate residual disease after surgery may improve patient outcome. Methods We used a colon carcinoma liver metastases model, in which CC531s colon carcinoma cells are injected into the portal circulation by a surgical procedure. As injected tumor cells are arrested in the liver, this model is suitable for investigating the interaction of tumor cells with the liver microenvironment. By administering tumor specific monoclonal antibodies (mAb) directly post-operatively, we were able to determine the effect of antibody therapy on eradication of arrested tumor cells and subsequent liver metastases outgrowth. Results We showed that post-operative treatment with tumor specific monoclonal antibodies (mAb) prevents liver metastases outgrowth. Antibody-dependent phagocytosis (ADPh) was the main mechanism involved, as enhanced uptake of tumor cells by innate mononuclear phagocytes in the liver was observed after mAb therapy. Furthermore, Kupffer cells (KC) were identified as the most prominent effector cells, as depletion of KC abolished therapeutic efficacy. This was partly compensated by monocytes when animals were treated with a high mAb dose, but monocytes were unable to phagocytose tumor cells when rats were treated with low mAb doses. Conclusions The finding that KC and monocytes can eliminate tumor cells through ADPh has important and promising clinical implications for designing new adjuvant therapies for patients undergoing CRC resection.