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

Liu WM, Henry JY, Meyer B, Bartlett JB, Dalgleish AG, Galustian C - Br. J. Cancer (2009)

Bottom Line: Allied to these, we have studied their effects on the molecular pathways associated with metastasis.Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular and Molecular Medicine, Department of Oncology, St George's, University of London, London SW17 0RE, UK. w.liu@sgul.ac.uk

ABSTRACT

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.

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Related in: MedlinePlus

Effect of IMiDs on the migration and invasion of cells. CT26 (A, B) and CMT93 (C) cells were re-suspended in FBS-free growth medium in the presence of absence of thalidomide, lenalidomide or pomalidomide (0–10 μM), and loaded into a chemotaxis chamber. The percentage of migratory and invasive cells was established by counting the cells in either compartment of a chemotaxis chamber after 16 h. Each column represents the mean and s.d. of at least three separate experiments. The effect of only 10 μM of each drug was assessed in CMT93 (panel C).
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fig3: Effect of IMiDs on the migration and invasion of cells. CT26 (A, B) and CMT93 (C) cells were re-suspended in FBS-free growth medium in the presence of absence of thalidomide, lenalidomide or pomalidomide (0–10 μM), and loaded into a chemotaxis chamber. The percentage of migratory and invasive cells was established by counting the cells in either compartment of a chemotaxis chamber after 16 h. Each column represents the mean and s.d. of at least three separate experiments. The effect of only 10 μM of each drug was assessed in CMT93 (panel C).

Mentions: The effect of IMiDs on the metastatic capabilities of CT26 and CMT93 cells was also examined by assessing the ability of cells to migrate across a permeable membrane towards 10% FBS in a 16 h period. (Figure 3A and C). The IMiDs were used at concentrations that were not cytotoxic at this short period of time, and the viability of cells in both compartments of the chemotaxis chambers was >90%. Migration in control wells, in which FBS was replaced with 0.1% BSA was minimal (%migration <2.4±1.5%). There was a concentration-dependent reduction in the migration of cells when cultured with IMiDs, which reach significance at the higher doses (P<0.001). In addition, there was no significant difference in the migratory capacity between the drugs tested.


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

Liu WM, Henry JY, Meyer B, Bartlett JB, Dalgleish AG, Galustian C - Br. J. Cancer (2009)

Effect of IMiDs on the migration and invasion of cells. CT26 (A, B) and CMT93 (C) cells were re-suspended in FBS-free growth medium in the presence of absence of thalidomide, lenalidomide or pomalidomide (0–10 μM), and loaded into a chemotaxis chamber. The percentage of migratory and invasive cells was established by counting the cells in either compartment of a chemotaxis chamber after 16 h. Each column represents the mean and s.d. of at least three separate experiments. The effect of only 10 μM of each drug was assessed in CMT93 (panel C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736839&req=5

fig3: Effect of IMiDs on the migration and invasion of cells. CT26 (A, B) and CMT93 (C) cells were re-suspended in FBS-free growth medium in the presence of absence of thalidomide, lenalidomide or pomalidomide (0–10 μM), and loaded into a chemotaxis chamber. The percentage of migratory and invasive cells was established by counting the cells in either compartment of a chemotaxis chamber after 16 h. Each column represents the mean and s.d. of at least three separate experiments. The effect of only 10 μM of each drug was assessed in CMT93 (panel C).
Mentions: The effect of IMiDs on the metastatic capabilities of CT26 and CMT93 cells was also examined by assessing the ability of cells to migrate across a permeable membrane towards 10% FBS in a 16 h period. (Figure 3A and C). The IMiDs were used at concentrations that were not cytotoxic at this short period of time, and the viability of cells in both compartments of the chemotaxis chambers was >90%. Migration in control wells, in which FBS was replaced with 0.1% BSA was minimal (%migration <2.4±1.5%). There was a concentration-dependent reduction in the migration of cells when cultured with IMiDs, which reach significance at the higher doses (P<0.001). In addition, there was no significant difference in the migratory capacity between the drugs tested.

Bottom Line: Allied to these, we have studied their effects on the molecular pathways associated with metastasis.Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular and Molecular Medicine, Department of Oncology, St George's, University of London, London SW17 0RE, UK. w.liu@sgul.ac.uk

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus