Contrasts between human and experimental melanomas.
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HYPERBARIC OXYGEN AND 5-FLUOROURACIL IN THE TREATMENT OF EXPERIMENTAL MELANOMA.
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Animals↗
Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis.
In this work we report the presence of intrametastatic smooth-muscle iso-alpha-actin (SMA)-expressing cells which appeared from the early stages of the hepatic metastasis process of intrasplenically injected B16 melanoma (B16M) cells. They formed a network of stromal cells among B16M cells, a very low percentage of them expressing desmin. In contrast, those parts of liver tissue unaffected by metastasis had perisinusoidal desmin-expressing quiescent hepatic stellate cells (qHSC) which did not express SMA. Exposure of freshly isolated rat quiescent hepatic stellate cells (qHSC) to B16M cell-conditioned medium (B16M-CM) leads to a progressive increase (P < .01) in the number of SMA-expressing cells, which was accompanied by a parallel reduction in the number of desmin-expressing cells. In addition, B16M-CM also contained chemotactic factor(s) which significantly (P < .01) increased (50%) in vitro qHSC migration and stimulated both [3H]thymidine and [3H]glucosamine uptake in qHSC. Moreover, B16M-CM also significantly (P < .01) enhanced qHSC secretion of matrix metalloproteinase-2 (MMP-2), and unknown chemotactic factor(s) enhancing in vitro migration of B16M cells. The results suggest that B16 melanoma releases qHSC-activating factors, which induce the appearance of metastasis-infiltrating myofibroblasts by a paracrine mechanism. Such cells showed cytoskeletal alterations which are associated with enhanced proliferation, glycosaminoglycan synthesis, MMP-2 secretion, and tumor-chemotactic factor production. Thus, tumor-activated qHSC may play an important role in melanoma cell motility and invasion during hepatic metastasis progression.
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Simultaneous blockade of VEGFR-1 and VEGFR-2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation.
Metastasis continues to be the major cause of morbidity and mortality in malignant melanoma. In our study, we explored whether inhibition of VEGFR-1 or VEGFR-2 signaling conveys distinct suppressive effects on B16 melanoma subcutaneous growth and metastasis formation. The inhibition of VEGFR-1 or -2 alone had no significant influence on both melanoma growth and metastasis formation. In contrast, simultaneous blockade of VEGFR-1 and -2 signaling strongly suppressed progression in both B16 tumor models. There was no expression of VEGFR-1 or -2 detectable on the B16 cells used, excluding the melanoma cells as direct therapeutic targets. Analyzing the contribution of progenitor-like cells during melanoma metastasis formation, we observed an enhanced proliferation and mobilization of VEGFR-1+ myeloid and VEGFR-2+ endothelial cells with progenitor potential by the induction of melanoma lung metastasis, which was not influenced by interference with VEGFR signaling. These results indicate that the antimetastatic effects exerted by combined inhibition of VEGFR-1 and -2 signaling were mediated via targeting cell populations other than progenitors only. Sole inhibition of VEGFR-1 signaling led to a strong reduction of the CD45-positive inflammatory infiltrate in the tumor tissue. However, the formation of lung metastasis was not affected, indicating that inhibition of the inflammatory response was not sufficient to efficiently block B16 melanoma metastasis development. Taken together, our data suggest that in the utilized B16 tumor models the blockade of both the inflammatory and the VEGFR-2-dependent angiogenic response are necessary to effectively inhibit solid tumor growth and formation of lung metastasis by B16 melanoma cells.
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Photoimmunology of experimental melanoma.
Increases in the incidence of cutaneous melanoma during the past few decades has drawn attention to the possible causes of this cancer. Although sunlight exposure has long been suspected of being a contributing factor, direct evidence of its participation has been difficult to obtain using epidemiological approaches. We have used murine models to investigate the possible contributions of UV radiation to the induction and pathogenesis of melanoma. Our studies demonstrate that UV radiation contributes to the induction of melanoma in a variety of ways, including an indirect, local effect on the skin. Recent evidence suggests that this indirect effect is immunologically mediated.
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Tumor vascularization in experimental melanomas: correlation between unenhanced and contrast enhanced power Doppler imaging and histological grading.
The purpose of this study was to evaluate the reliability of unenhanced and enhanced power Doppler sonography in visualization of intratumoral angioneogenesis. Thirty-seven malignant melanomas, which had been implanted intra- or subcutaneously in 22 mice, were examined. Various B-mode criteria, power Doppler criteria and spectral Doppler parameters were evaluated before and after IV-application of the d-galactose-based contrast agent Levovist. After sonographic examination, all tumors were analyzed histologically with semiquantitative grading of tumoral vascularization. Unenhanced, in 70% of the tumors, no intratumoral vessels were visible using power Doppler, but only in 11% of the intracutaneous and in 0% of the subcutaneous after injection of the contrast agent. The enhanced mode was definitely superior to unenhanced Doppler in showing the intratumoral vascularity. The intratumoral vascular structure could be sufficiently analyzed in 30% of all tumors by unenhanced Doppler, but in 92% enhanced. The mean percentage vessel area increased about 433% after application of Levovist (intracutaneous: 485%, subcutaneous: 280%). Despite the missing direct correlation between the sonographically and histologically determined grade of tumor vascularization (Pearson's correlation unenhanced 0,356, p <.05/enhanced 0.395, p <.05), the correlation between the percentage vessel area and the histologic grade of vascularization was improved after application of the contrast agent (Pearson's correlation unenhanced 0.347, p <.05/enhanced 0.686, p <.01). We did not find a significant direct correlation between histologically and sonographically determined degree of vascularization. However, the correlation was improved using a d-galactose-based signal-enhancing agent in power Doppler sonography.
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Gadolinium neutron-capture therapy using novel gadopentetic acid-chitosan complex nanoparticles: in vivo growth suppression of experimental melanoma solid tumor.
The potential of gadolinium neutron-capture therapy (Gd-NCT) for cancer was evaluated using chitosan nanoparticles as a novel gadolinium device. The nanoparticles, incorporating 1200 microg of natural gadolinium, were administered intratumorally twice in mice bearing subcutaneous B16F10 melanoma. The thermal neutron irradiation was performed for the tumor site, with the fluence of 6. 32x10(12) neutrons/cm(2), 8 h after the second gadolinium administration. After the irradiation, the tumor growth in the nanoparticle-administered group was significantly suppressed compared to that in the gadopentetate solution-administered group, despite radioresistance of melanoma and the smaller Gd dose than that administered in past Gd-NCT trials. This study demonstrated the potential usefulness of Gd-NCT using gadolinium-loaded nanoparticles.
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Positron emission tomography of experimental melanoma with.
Positron emission tomography (PET) has evolved as a new diagnostic modality in cancer patients. Thioureylenes, such as thiouracil and methimazole, are known to be incorporated into growing melanin and selectively retained in melanotic melanoma. In the present study we used [(76)Br]5-bromo-2-thiouracil as tracer for PET imaging of human and murine melanotic melanoma transplanted subcutaneously into rats. The melanomas were clearly depicted 1 day after the injection, when [(76)Br]5-bromo-2-thiouracil was retained in the tumors though the overall radioactivity concentration in the body had declined. Accumulation of (76)Br was also seen in bladder, liver, and kidney. In addition, the rats were simultaneously injected with [(125)I]5-iodo-2-thiouracil and the tissue distribution of radioactivity was mapped by whole-body autoradiography. The results confirmed the selective uptake of thiouracil in the melanoma where the concentration of (125)I-radioactivity was about three-fold higher than that in the liver and lungs. These results show the possibility of using [(76)Br]5-bromo-2-thiouracil for PET diagnostics of melanoma, including dosimetry, prior to targeted therapy using [(131)I]5-iodo-2-thiouracil or [(211)At]5-astato-2-thiouracil.
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Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis.
Myofibroblasts infiltrate malignant liver tumors, although their pathogenic implications are unclear. Immunohistochemical detection of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP), and CD31 and CD34 expression was used to analyze the contribution of myofibroblasts to angiogenesis in hepatic metastasis produced by intrasplenically-injected B16 melanoma (B16M). Because activated hepatic stellate cells (HSCs) are oxygen-sensing myofibroblasts producing vascular endothelial growth factor (VEGF), the effect of B16M and human A375 melanoma supernatants on VEGF production by immortalized rat HSC line T6 and primary cultured human HSCs also was studied under an hypoxic atmosphere mimicking a tumor microenvironment. Myofibroblast infiltration preceded endothelium recruitment in avascular micrometastasis and generated specific stroma for sinusoidal-type and portal-type angiogeneses. Thereafter, myofibroblasts and endothelial cells colocalized within both angiogenic patterns and their numerical densities correlated with metastasis development. Myofibroblasts often were GFAP-positive, suggesting an HSC origin. Melanoma supernatants stimulated VEGF messenger RNA and protein synthesis by HSCs. These effects were potentiated by hypoxia. VEGF up-regulation was accompanied by increased expression of cyclooxygenase type 2 (COX-2) and PGE2 synthesis. HSC production of VEGF decreased under COX-2 inhibition, whereas it was increased by exogenous PGE2. The high VEGF expression in HSCs induced by melanoma factors and hypoxia resulted in mitogenic, antiapoptotic, and motogenic stimulation of both murine hepatic sinusoidal endothelium and human umbilical vein endothelium. In conclusion, temporal and positional relationships evolve between myofibroblast and endothelium recruitment during metastasis development. Mechanistically, hypoxic induction of VEGF in tumor-activated HSCs may create a proangiogenic microenvironment, facilitating endothelial cell recruitment and survival during hepatic metastasis transition from an avascular to a vascular stage.
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Ganglioside profiles of experimental melanomas and of their melanosomal fractions.
We compared ganglioside profiles of animal tumours (B16 and Cloudman S91 murine melanomas, Bomirski Syrian hamster melanoma), which are widely used as models of human melanoma, and of their melanosomal fractions. A ganglioside fraction was extracted and purified and the amount of each component ganglioside was assessed by thin-layer chromatography. GM3 was the dominant ganglioside species in the murine melanomas studied. Unlike human melanomas, the GD3 expression in mouse melanomas was low. GD3 and GM3 were major gangliosides in Bomirski hamster melanoma. Alkali-labile O-acetyl-GD3, a melanoma-specific ganglioside, was detected only in Bomirski melanoma. GD2, which in human melanoma is seen as a distinct signal of tumour progression, was not found in the animal melanomas studied. Melanosomes isolated from B16 and Bomirski melanomas contained GM3 and GD3 as their major ganglioside components. These data extend the group of common antigenic determinants shared by melanosomes and cell surface of pigment cells.
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Light and electron microscopic findings on experimental melanomas after hyperthermia at 50 degrees C.
The effect of hyperthermia, 50 degrees C applied for 5 min, on the development of lesions in hamster Greene melanomas was investigated. Hyperthermia was induced by a laser that produced radiation at 780-880 nm. Hamster melanomas were also examined after arrest of the blood circulation to differentiate between heat-induced lesions and those caused by ischaemia due to vascular occlusion. Tumours were removed 5 and 30 min and 1, 3, 6 and 24 h after thermotherapy. The cytotoxic effects of heat and ischaemia were examined by light and electron microscopy. Hyperchromatic nuclear staining, the first hyperthermia-induced lesion, was detected in the superficial layers of the tumour 5 min after heat treatment. The lesions had progressed to severe pyknosis and extended into deeper layers of the tumour 1 h after hyperthermia. At 24 h necrosis was observed at a depth of 6 mm. The hyperthermia-induced lesions differed markedly from the ischaemia-induced lesions, in that the latter showed early mitochondrial damage but nuclear pyknosis did not become manifest until 3 h after arrest of the blood circulation.
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The high-affinity IgG receptor, FcgammaRI, plays a central role in antibody therapy of experimental melanoma.
We examined the role of FcgammaR in antibody therapy of metastatic melanoma in wild-type and different FcgammaR knock-out mice. Treatment of B16F10-challenged wild-type mice with TA99 antibody specific for the gp75 tumor antigen resulted in a marked decrease in numbers of lung metastases. Treatment of individual FcgammaR knock-out mice revealed the high-affinity IgG receptor, FcgammaRI (CD64), to represent the central FcgammaR for TA99-induced antitumor effects. The potential of immune-modulating agents to further enhance the protective effect induced by monoclonal antibody (mAb) TA99 was examined in combination treatments consisting of mAb TA99 and a TLR-4 agonist, monophosphoryl lipid A (MPL). MPL did potently boost TA99 antibody-induced effects, and combination therapy was, again, found to be dependent on the presence of FcgammaRI.
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[Heparin inhibits metastatization of experimental melanoma].
Heparin treatment, at human equivalent doses, modulates coagulation parameters in mice similarly to the human situation. Heparins were tested in various melanoma metastasis models for their antimetastatic activity. Heparins were active against melanoma metastasis without influencing the primary tumor. Tumor cell-induced platelet aggregation was not the primary target of heparins, since melanoma cells were not active in this respect. Our results support the notion that heparins have antimetastatic activity.
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Peritumoural IL-4 treatment induces systemic inhibition of tumour growth in experimental melanoma.
We have examined the ability of interleukin-4 (IL-4) to inhibit the growth of the B.16 melanoma in C57BL/6 mice. Tumours were allowed to become established and then treated locally with 50 ng/day IL-4. Treatment was continued for 7 days and then the tumours were removed and weighed. The results showed that recombinant murine IL-4 (rmIL-4) strongly inhibited tumour growth, with some complete resolutions. In addition, the effect of IL-4 treatment was seen to be systemic; in mice bearing two tumours (neck and thigh), which had been innoculated simultaneously, treatment at the neck site resulted in reduced tumour growth at both sites. This effect was accompanied by an increase in the proportion of lymphocytes in the spleen, particularly T-cells, although tumours at neither site showed much evidence of leucocytic infiltration. These results suggest that local treatment with IL-4 is able to profoundly reduce the rate of tumour growth, even of nodules not receiving treatment directly.
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IL-2 inhibits the induction of systemic antitumour immunity by IL-4 in the peritumoural treatment of experimental melanoma.
We have examined the relative abilities of interleukin-4 (IL-4) and interleukin-2 (IL-2) to inhibit the growth of the B.16 melanoma in C57BL/6 mice. Tumours were allowed to become established and then treated peritumourally with either IL-4 or IL-2, or a combination of IL-4 plus IL-2. Treatment was continued for 7 days and then the tumours were removed and weighed. The results showed that IL-4 strongly inhibited tumour growth in 83% of individuals, but complete resolution was observed in only 18%. In the IL-2 treated groups, the percentage of growth-inhibited tumours was markedly less (50%), with 14% complete resolutions. In the IL-4+IL-2 treated tumours resolution was again different, such that only 57% of tumours were smaller than those seen in the controls but there was a high number bearing no measurable tumour (25%). In addition, of the three treatments described, only peritumoural administration of IL-4 alone could mediate the induction of systemic protection from tumour growth. These results suggest that IL-4 and IL-2 have different mechanisms of action and that IL-2 may antagonise the effect of IL-4 such that the action of the two materials when combined is highly unpredictable.
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[Inhibitory effects of two oligosaccharides on murine melanoma experimental metastasis].
OBJECTIVE: To observe the effects of a chemically synthesized tetrose and a natural yeast mannan on mouse melanoma experimental liver metastasis. METHODS: After treated with 4 mg tetrose (tetrose group) or 4 mg mannan (mannan group) for 30 minutes at 37 degrees C, 0.5 ml 1 x 10(6)B16-MBK melanoma cells were injected intraspleen. 55 days later, melanoma metastasis nodes in the surfaces of the liver and other organs as well as mouse survival time were observed. RESULTS: Of 6 mice in control (B16 cell+PBS), 4 died naturally within 55 days, 2 were dissected in the 55th day. All of the 6 mice had metastases in the livers, the total number of the melanoma nodes on each liver surface ranged from 2 to 30, with the largest one fused to the whole liver. One mouse had a neoplasm in the remnant site of injection, 3 had metastases in lungs, while of the 6 mice in the tetrose group, one died on the 50th day on injection. In mannan group, all of the 6 mice survived and no metastasis was seen except the largest diameter of < 1 mm of 2 liver nodes in one mouse. Neither tetrose nor mannan group had metastasis of the liver, and the weights of liver in the two groups were significantly lower than in the control. CONCLUSION: Both tetrose and mannan had the effects in blocking melanoma experimental liver metastasis, inhibiting transmigration of the liver, and prolonging the survival time of the mouse.
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Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis.
Spontaneous and experimental metastasis can be effectively inhibited by the widely used anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Whereas previous attention has focused on P-selectin-dependent tumor-cell-platelet interactions in blood-borne metastasis, we sought to address the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Transplantation of bone marrow from P-selectin-deficient into wild-type mice conveyed inhibition of ex-perimental melanoma metastasis. However, the extent to which bone marrow-conferred lack of platelet P-selectin expression attenuated melanoma lung metastasis was significantly less than that seen in P-selectin-deficient mice, suggesting that endothelial P-selectin expression may additionally contribute to formation of hematogenous metastases. This assumption was supported by our intravital microscopy studies, in which a significant proportion of melanoma cells were capable of directly interacting with postcapillary venules of the murine ear in a P-selectin-dependent manner. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, further supporting the concept that endothelial P-selectin expression may represent an additional target of heparin action in experimental melanoma lung metastasis.
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[Morphological changes in experimental melanoma B-16 effected by a conjugate of polyvinylpyrrolidone and metal-organic complex of copper and melphalan].
Data on morphological alterations in experimental melanoma B-16 induced by conjugate of polyvinylpyrrolidone and metal-organic complex of copper and melfalon are presented. The antitumor effect of the synthetic conjugate, which inhibits melanoma-16 growth, is adequately tolerated by bone marrow cells. Conjugate accumulation among the dividing cells inhibits the proliferatrive capability of malignant cells and causes other specific morphological changes to occur. It was found that polyvinylpyrrolidone conjugate can be used as a carrier whenever there is a problem of making certain drugs soluble and, thus, more marketable.
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