Tissue-specific differential antitumour effect of molecular forms of fractalkine in a mouse model of metastatic colon cancer.
OBJECTIVE
Fractalkine, a chemokine that presents as both a secreted and a membrane-anchored form, has been described as having tumour-suppressive activities in standard subcutaneous models. Here, we investigate the antitumour effect of fractalkine, in its three molecular forms, in two orthotopic models of metastatic colon cancer (liver and lung) and in the standard subcutaneous model.


METHODS
We have developed models of skin tumours, liver and pulmonary metastasis and compared the extent of tumour development between C26 colon cancer cells expressing either the native, the soluble, the membrane-bound fractalkine or none.


RESULTS
The native fractalkine exhibits the strongest antitumour effect, reducing the tumour size by 93% in the skin and by 99% in the orthotopic models (p<0.0001). Its overall effect results from a critical balance between the activity of the secreted and the membrane-bound forms, balance that is itself dependent on the target tissue. In the skin, both molecular variants reduce tumour development by 66% (p<0.01). In contrast, the liver and lung metastases are only significantly reduced by the soluble form (by 96%, p<0.002) whereas the membrane-bound variant exerts a barely significant effect in the liver (p = 0.049) and promotes tumour growth in the lungs. Moreover, we show a significant difference in the contribution of the infiltrating leukocytes to the tumour-suppressive activity of fractalkine between the standard and the orthotopic models.


CONCLUSIONS
Fractalkine expression by C26 tumour cells drastically reduces their metastatic potential in the two physiological target organs. Both molecular forms contribute to its antitumour potential but exhibit differential effects on tumour development depending on the target tissue.
Vitale
S
S
INSERM U638, Faculté de Médecine, 28 Avenue de Valombrose, 06107 Nice Cedex 02, France.
Cambien
B
B
Karimdjee
B F
BF
Barthel
R
R
Staccini
P
P
Luci
C
C
Breittmayer
V
V
Anjuère
F
F
Schmid-Alliana
A
A
Schmid-Antomarchi
H
H
D000818:Animals; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D014162:Transfection
D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; D008565:Membrane Proteins