Interleukin 1 (IL-1)-dependent melanoma hepatic metastasis in vivo; increased endothelial adherence by IL-1-induced mannose receptors and growth factor production in vitro.

BACKGROUND: The growth of cancer cells in inflammatory tissue is often observed. This can be the result of favorable conditions for endothelial cell adherence and/or increased production of local growth factors. PURPOSE: The role of the proinflammatory cytokine interleukin 1 (IL-1) in the prometastatic and growth-promoting environment of inflammation was studied in vivo, and the mechanism of cytokine action was studied in vitro as well. METHODS: Systemic inflammation was induced by the intravenous injection of IL-1 beta or lipopolysaccharide (LPS), and the hepatic metastasizing ability of B16 melanoma (B16) cells following intrasplenic injection was studied. IL-1 receptor blockade was accomplished with the use of the IL-1 receptor antagonist (IL-1Ra). In vitro, IL-1Ra was used to assess the mechanism for prometastasis and growth promotion of cultured hepatic sinusoidal endothelium stimulated with LPS. RESULTS: There was a statistically significant (P < .01) enhancement in the parameters of hepatic metastasis when B16 cells were injected intrasplenically either 4 hours after IL-1 injection or 6 or 12 hours after LPS injection. IL-1Ra pretreatment reduced IL-1-induced enhancement of metastasis by 73%-87% and completely inhibited the augmentation of metastasis following LPS injection. In vitro, the adherence of melanoma cells to LPS-treated endothelium increased nearly twofold but was completely abrogated when IL-1Ra was added before LPS. Similar to melanoma adherence, a 2.5-fold increase (P < .05) in functional mannose receptors was observed with LPS treatment but was prevented by the addition of IL-1Ra did not affect basal mannose-receptor activity in unstimulated epithelium. Mannose-receptor activity and B16 cell adherence significantly correlated (r = .9) with LPS treatment. Conditioned medium from LPS-stimulated epithelium augmented B16 cell proliferation compared with control conditioned medium (P < .01). Production of B16 cell growth factor(s) was markedly reduced (P < .01) when IL-1Ra was added. CONCLUSIONS: These results demonstrate that systemic inflammation induces an enhancement of melanoma cell metastasis and growth by IL-1-dependent mechanisms in vivo. In vitro, the mechanism(s) is consistent with IL-1-mediated increase in expression of mannose receptors and production of tumor cell growth factor(s) from the endothelium. IMPLICATIONS: Given the multiple and complex cytokine cascade induced in vivo and in vitro during LPS-induced systemic inflammation, IL-1 plays a strategic role. Since IL-1Ra is without side effects in humans, studies on intraoperative infusion of IL-1Ra during tumor resection may be indicated.

alpha-1-Antitrypsin phenotypes among breast cancer patients in the Basque population.

One of the main functions of alpha 1-antitrypsin (A1AT) is to inhibit the activity of most proteases. It has been suggested that a deficiency in this protein may favor invasion by cancer cells--consequently, individuals with A1AT-deficient alleles (null, S and Z) may be at greater risk of tumoral invasion due to their lower capacity of response to proteolytic enzymes. This work examines the frequencies of A1AT phenotypes in breast cancer (BC) patients. A sample of patients classified as having infiltrative ductal carcinoma was chosen to be studied as it is a highly invasive tumor, and a sample of patients with BC and a familial history of cancer has also been studied. An increase in the frequency of A1AT-deficient phenotypes was not observed in any of the three groups. One possible explanation could be the immunosuppressive activity of A1AT.

Noncorrelation between implantation and growth of tumor cells for their final metastatic efficiency.

We have measured the relative contribution of implantation and focal growth metastatic phenomena on the hepatic colonization process of intrasplenically injected B16 melanoma or Lewis lung carcinoma (LLC) tumor cells. To do this, an experimental variation of the parental tumor cell phenotype (seed factor) was performed by a selection of 10 times passaged hepatic-metastasizing tumor cells and changes in biological features of host tissue (soil) were induced following the treatment of the mice with ciclosporin, Thymostimulin, Bleomycin, silica particles or 17 alpha-ethynylestradiol prior to tumor injection. Implantation efficiency of selected variants was highly increased but, while the focal metastatic growth efficiency did not vary in LLC variants, in selected B16 melanoma cells it was clearly higher. In all the pretreated animals final metastatic volume varied with respect to the controls. In some mice, implantation efficiency was increased but this effect did not always determine later increments in the final metastatic volume. In other mice, focal growth of metastases was reduced with respect to the controls without correlative reductions in the final metastatic volume. In general, changes of final metastatic volume in the liver were mostly dependent upon the ability of tumor cells to successfully implant. Thus, final metastatic volume seems to depend on the sum of two relatively independent colonization phenomena: tumor cell implantation and focal growth of metastases.