Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

• Published in: British journal of cancer 2009-09, Vol.101 (5), p.803-812
• Main Authors: Liu, W M, Henry, J Y, Meyer, B, Bartlett, J B, Dalgleish, A G, Galustian, C
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell Movement - drug effects; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Cytokines - biosynthesis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Drug Screening Assays, Antitumor; Drugs; Epidemiology; FDA approval; Female; Gastroenterology. Liver. Pancreas. Abdomen; Immunoblotting; Immunohistochemistry; Immunologic Factors - therapeutic use; Lenalidomide; Medical research; Medical sciences; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Medicine; Multiple myeloma; Neoplasm Invasiveness - prevention & control; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - prevention & control; Oncology; Signal Transduction - drug effects; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thalidomide - analogs & derivatives; Thalidomide - therapeutic use; Translational Therapeutics; Tumor Cells, Cultured; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605206

Background: Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer. Methods: As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro . Allied to these, we have studied their effects on the molecular pathways associated with metastasis. Results: Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency. Conclusions: These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.