Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs).
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.
Liu
W M
WM
Division of Cellular and Molecular Medicine, Department of Oncology, St George's, University of London, London SW17 0RE, UK. w.liu@sgul.ac.uk
Henry
J Y
JY
Meyer
B
B
Bartlett
J B
JB
Dalgleish
A G
AG
Galustian
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000627:therapeutic use*; D000077269:Lenalidomide; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016207:Cytokines; D007155:Immunologic Factors; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide