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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 the IMiDs on pulmonary metastases. CT26 cells were injected into the tail vein of BALB/c mice. The effect of thalidomide, lenalidomide and pomalidomide administered daily IP on pulmonary metastases was assessed on day 14 (A). There were significantly fewer metastatic nodules in the lungs resected from treated animals (P<0.001 vs controls). Representative lungs are also shown. Similar reductions in metastatic nodules of CMT93 were observed in mice treated with the drugs (B). Each data point represents the means and ranges of five animals. The effect on metastasis of pre-treating CT26 cells for 3 days with 10μM lenalidomide was also studied (C), where the shaded bars indicate treatment with lenalidomide. Pre-treatment (treatment protocol C) resulted in fewer nodules.
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fig6: Effect of the IMiDs on pulmonary metastases. CT26 cells were injected into the tail vein of BALB/c mice. The effect of thalidomide, lenalidomide and pomalidomide administered daily IP on pulmonary metastases was assessed on day 14 (A). There were significantly fewer metastatic nodules in the lungs resected from treated animals (P<0.001 vs controls). Representative lungs are also shown. Similar reductions in metastatic nodules of CMT93 were observed in mice treated with the drugs (B). Each data point represents the means and ranges of five animals. The effect on metastasis of pre-treating CT26 cells for 3 days with 10μM lenalidomide was also studied (C), where the shaded bars indicate treatment with lenalidomide. Pre-treatment (treatment protocol C) resulted in fewer nodules.

Mentions: The propensity of CRC cells to spontaneously seed into and grow within the lungs of mice after tumour cell injection into the tail vein was used as the in vivo model of metastasis. The method is widely used, and easily defines metastatic potential – that is the ability of tumour cells to seed, evade host immuno-surveillance and to interact with the microenvironment by receiving growth and survival signals from it (Khanna and Hunter, 2005). Results showed that metastasis into the lung was significantly decreased in BALB/c mice treated with IMiDs compared with that in untreated mice (P<0.001 in all cases) (Figure 6A). As an example, the average number of pulmonary nodules from 28 untreated BALB/c mice was 95, whereas the average number in 15 mice treated daily with 50 mg kg−1 of thalidomide was 17. These data were recapitulated in C57BL/6 mice injected with the CMT93 cell line, with significant reductions in the number of pulmonary nodules after treatment with thalidomide, lenalidomide or pomalidomide (Figure 6B).


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 the IMiDs on pulmonary metastases. CT26 cells were injected into the tail vein of BALB/c mice. The effect of thalidomide, lenalidomide and pomalidomide administered daily IP on pulmonary metastases was assessed on day 14 (A). There were significantly fewer metastatic nodules in the lungs resected from treated animals (P<0.001 vs controls). Representative lungs are also shown. Similar reductions in metastatic nodules of CMT93 were observed in mice treated with the drugs (B). Each data point represents the means and ranges of five animals. The effect on metastasis of pre-treating CT26 cells for 3 days with 10μM lenalidomide was also studied (C), where the shaded bars indicate treatment with lenalidomide. Pre-treatment (treatment protocol C) resulted in fewer nodules.
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Related In: Results  -  Collection

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fig6: Effect of the IMiDs on pulmonary metastases. CT26 cells were injected into the tail vein of BALB/c mice. The effect of thalidomide, lenalidomide and pomalidomide administered daily IP on pulmonary metastases was assessed on day 14 (A). There were significantly fewer metastatic nodules in the lungs resected from treated animals (P<0.001 vs controls). Representative lungs are also shown. Similar reductions in metastatic nodules of CMT93 were observed in mice treated with the drugs (B). Each data point represents the means and ranges of five animals. The effect on metastasis of pre-treating CT26 cells for 3 days with 10μM lenalidomide was also studied (C), where the shaded bars indicate treatment with lenalidomide. Pre-treatment (treatment protocol C) resulted in fewer nodules.
Mentions: The propensity of CRC cells to spontaneously seed into and grow within the lungs of mice after tumour cell injection into the tail vein was used as the in vivo model of metastasis. The method is widely used, and easily defines metastatic potential – that is the ability of tumour cells to seed, evade host immuno-surveillance and to interact with the microenvironment by receiving growth and survival signals from it (Khanna and Hunter, 2005). Results showed that metastasis into the lung was significantly decreased in BALB/c mice treated with IMiDs compared with that in untreated mice (P<0.001 in all cases) (Figure 6A). As an example, the average number of pulmonary nodules from 28 untreated BALB/c mice was 95, whereas the average number in 15 mice treated daily with 50 mg kg−1 of thalidomide was 17. These data were recapitulated in C57BL/6 mice injected with the CMT93 cell line, with significant reductions in the number of pulmonary nodules after treatment with thalidomide, lenalidomide or pomalidomide (Figure 6B).

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