Effects of 1,25-Dihydroxyvitamin D₃ on Tumor Cell Invasion to the Extracellular Matrix in Human Fibrosarcoma HT1080 Cells and Its Correlation with Laminin

Abstract

We investigated the role of the active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], in promoting tumor cell invasiveness through the extracellular matrix, and showed that 1,25(OH)₂D₃-induced reduction of laminin production by the cells was correlated with the inhibitory effects of the hormone on tumor cell invasiveness. 1,25(OH)₂D₃ significantly inhibited invasiveness through the matrix, type IV colla-genolytic and migratory activity, but not cell attachment to the matrix in human fibrosarcoma HT1080 cells. The 1,25(OH)₂D₃-induced inhibition showed the same dose dependency and magnitude for invasiveness as for the effects on type IV collagenolysis and cell migration. 1,25(OH)₂D₃ inhibited laminin production from the cells in a dose-dependent manner. The inhibitory effects of 1,25(OH)₂D₃ on the invasiveness, type IV collagenolysis and cell migration appeared to parallel the hormone-induced reduction of laminin production. Antilaminin monoclonal antibody, blocking the activity of laminin in the culture medium, inhibited HT1080 cell invasiveness. In the presence of exogenous laminin, 1,25(OH)₂D₃-induced inhibition of invasion was not observed. These findings suggest that 1,25(OH)₂D₃ acts on HT1080 cells, inhibiting the expression of laminin from the cells, and that the reduced laminin expression leads to the inhibition in the type IV collagenolytic and migratory activity of the cells, and consequently, to the inhibition of invasiveness through the extracellular matrix.

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

“…Other mechanisms, such as regulation of the proteolytic enzymes, as mentioned above, modulation of extracellular matrix proteins and adhesion molecules, are therefore likely be involved. The latter hypothesis is in accordance with the observation that 1,25(OH) 2 D 3 reduces the expression of laminin in human fibrosarcoma cells and the number of laminin-binding integrins and the expression of very late antigen-4 (VLA-4) in human melanoma cells (184,191,192).…”

“…The anti-invasive effect of vitamin D has further been substantiated by other studies showing that these compounds are able to inhibit cancer cell progression by interfering with specific steps in the metastatic cascade, including the proteolytic enzymes. In the mouse B16 melanoma and the human HT1080 fibrosarcoma cell lines, inhibition of invasion by vitamin D has been shown to be associated with a decreased activity of the type IV collagenases (184,185). Moreover, in the human MDA-MB-231 breast cancer cell line, treatment of the cells with vitamin D was found to result in a diminished activity of the matrix metalloproteinase MMP-9 and the two serine proteases urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) concomitant with a reduced invasiveness of the cells.…”

“…Also, a direct relationship between the antiproliferative effect of vitamin D and the level of receptors has been observed in some cell types in vitro, while in others there seems to be no correlation (Reviewed in (61)). However, despite being unable to respond to the growth inhibiting effect of vitamin D, these cells may still be capable of responding to other effects of vitamin D, such as induction of differentiation and inhibition of invasion (70,129,184).…”

Seocalcitol (EB 1089) A Vitamin D Analogue of Anti-cancer Potential. Background, Design, Synthesis, Pre-clinical and Clinical Evaluation

“…Of particular interest is the effect of vitamin D compounds on collagenases, as these enzymes exhibit the ability to degrade extracellular matrix. In human HT1080 fibrosarcoma cells, treatment with 1α,25(OH) 2 D 3 for 3 days resulted in a dose-dependent decrease of type IV collagenolytic activity concomitant with a reduction of laminin mRNA and protein expression, a reduced migratory activity and an inhibition of invasiveness through extracellular matrix-coated filters [137]. This observation was supported by a study undertaken in human cancer cells of follicular thyroid origin.…”

Vitamin D3 modulation of plasminogen activator inhibitor type-1 in human breast carcinomas under organ culture

“…The prognosis of breast and other cancers is ultimately determined by the tumor ability to invade and metastasize. Although the modulatory effects of VD3 or its analogous on the invasive process have been shown in a variety of human cancer cell types, relatively little is known regarding the molecular basis for the anti-invasive activity of VD3 in breast carcinomas [21,29,32,37,41,46].…”