Prevention of human prostate tumor metastasis in athymic mice by antisense targeting of human angiogenin.

PURPOSE: Angiogenin is a potent positive mediator of neovascularization, a process required for both primary tumor growth and metastasis. In the present study, the effect of a fully phosphorothioated antisense oligodeoxynucleotide, designated JF2S, targeting the AUG translation initiation codon region of human angiogenin, on human prostate tumor development and metastasis in athymic mice was examined. EXPERIMENTAL DESIGN: JF2S was evaluated for its capacity to affect in vitro synthesis of angiogenin and subsequent tumorigenicity of transiently transfected prostate tumor cells in mice. In vivo treatment experiments were then conducted in which JF2S was used to prevent formation of tumors in an ectopic model and metastasis in an orthotopic model. RESULTS: Transient transfection of tumor cells with JF2S inhibited both angiogenin gene expression in vitro and tumorigenicity of these transfected cells in athymic mice. In therapy experiments, local treatment with JF2S completely protected mice from developing prostate tumors after s.c. injection of PC-3 human prostate tumor cells (P < 0.0001, survivor analysis). Most importantly, systemic prophylactic administration of JF2S prevented, in 47% of mice, formation of regional iliac lymph node micrometastases arising from primary tumors growing in the more natural orthotopic prostate setting (P = 0.0003, Fisher's exact test). Furthermore, total protection from regional metastasis occurred in those mice in which JF2S treatment successfully diminished human angiogenin expression in vivo. Tumor-associated angiogenesis was also impaired by JF2S treatment. When therapy was delayed until all of the mice harbored primary tumors in the prostate, the incidence of regional metastasis was still significantly decreased (P < 0.005, survivor analysis). CONCLUSIONS: These findings demonstrate that human prostate cancer establishment and spread in athymic mice is extremely susceptible to targeted disruption of tumor-derived human angiogenin gene expression. Therefore, angiogenin is a valid target against which to devise preventative strategies for prostate cancer metastasis.

Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: role of LEF-1 in melanoma with increased metastatic potential.

A constitutive complex of beta-catenin and LEF-1 has been detected in melanoma cell lines expressing either mutant beta-catenin or mutant APC (Rubinfeld et al., Science, 275, 1790-1792, 1997). However, it has been recently reported that beta-catenin mutations are rare in primary malignant melanoma, but its nuclear and/or cytoplasmic localization, a potential indicator of Wnt/beta-catenin pathway activation, is frequently observed in melanoma (Rimm et al., Am. J. Pathol., 154, 325-329, 1999). In human malignant melanoma, the appearance of the tumorigenic phase represents a capacity for metastasis and is the significant phenotypic step in disease progression. Cell motility in invasive melanoma is thought to play a crucial role in metastatic behavior. In this work, we sought to determine which transcription factor of the LEF/TCF family was preferentially involved in human melanoma from different stages of tumor progression. We show that LEF-1 mRNA expression is predominant in highly migrating cells from metastatic melanomas. These actively migrating melanoma cells showed nuclear and cytoplasmic accumulation of beta-catenin and active transcription from a reporter plasmid of the LEF/TCF binding site. These results may provide a new insight into the role of the Wnt/beta-catenin signaling pathway in the tumor progression of malignant melanoma.

Selective expression of FLIP in malignant melanocytic skin lesions.

FLIP (FLICE Inhibitory Protein) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits cell death mediated by all death receptors including Fas and TRAIL. FLIP has recently been shown to favor tumor growth and immune escape in mouse tumor models. We analyzed FLIP expression by immunohistochemistry in a panel of 61 benign and malignant human melanocytic skin lesions. FLIP expression was undetectable in all but one benign melanocytic lesion (31/32, 97%). In contrast, FLIP was strongly expressed in most melanomas (24/29 = 83%). Overexpression of FLIP by transfection in a Fas- and TRAIL-sensitive human melanoma cell line rendered this cell line more resistant to death mediated by both TRAIL and FasL. Selective expression of FLIP by human melanomas may confer in vivo resistance to FasL and TRAIL, thus representing an additional mechanism by which melanoma cells escape immune destruction.

Changes in cellular motility and cytoskeletal actin in fibroblasts from patients with chronic venous insufficiency and in neonatal fibroblasts in the presence of chronic wound fluid.

PURPOSE: Fibroblasts (fb) play an important role in wound healing involving motility, contraction, fibrosis, and expression of the cytoskeletal protein alpha-smooth muscle actin (alpha-sma). Patients with chronic venous insufficiency (CVI) are known to have dermal changes and impaired venous ulcer healing. To investigate whether these dermal-fb have an altered ability to migrate and whether chronic wound fluid from venous ulcers alters neonatal fb motility, we examined cell migration and alpha-sma. METHODS: Fibroblasts were cultured from the margin of venous ulcers (du-fb, n = 4, CEAP 6), from patients with venous reflux without ulcer (dr-fb, n = 5, CEAP 2), and from the ipsilateral thigh of the same patients with (pu-fb) and without (pr-fb) ulcer, respectively. The abbreviations used are p and d, which represent proximal and distal, respectively; u and r represent ulcer and reflux, respectively. Neonatal foreskin fibroblasts (nf-fb) were exposed to chronic venous ulcer wound fluid (CVUWF, 300 microg protein/mL, n = 3) or bovine serum albumin (BSA, control). Fibroblast motility was determined by means of time-lapse photo-images, and the rate (micrometer per hour) was calculated. Immunohistochemistry for alpha-sma was analyzed with confocal laser microscopy. RESULTS: The rate of motility (micrometer per hour +/- SEM) was decreased for both du-fb (11.4 +/- 0.7) and dr-fb (13.8 +/- 0.6), when compared with pu-fb (21.9 +/- 0.9) and pr-fb (24.7 +/- 1.1), respectively. The motility rate for nf-fb was lower in CVUWF (24.7 +/- 2.0) than in BSA (37.1 +/- 6.7). An elevated level of microfilament bundles of alpha-sma for both du-fb and dr-fb, compared with those of pu-fb and pr-fb, and also in nf-fb treated with CVUWF was demonstrated by means of immunohistochemistry. CONCLUSION: These data demonstrate a reduced motility in the dermal fb of patients with CVI. Patients with reflux disease without ulcer are predisposed to these changes. Furthermore, it appears that CVUWF causes changes in motility and alpha-sma expression in nf-fb as demonstrated in du-fb. These findings suggest that reduced motility and CVUWF, representing the microenvironment of venous ulcers, play a significant role in impaired wound healing.

Expression of PGP 9.5 in granular cell nerve sheath tumors: an immunohistochemical study of six cases.

BACKGROUND: Protein gene product 9.5 (PGP 9.5) is expressed in brain at 20 to 50 times the levels detected in other organs. Immunohistochemical studies reveal this protein is localized to both central and peripheral neurons. Recently, PGP 9.5 is reported to be a useful marker for cellular neurothekeomas. Herein we test whether PGP 9.5 is a new marker for granular cell nerve sheath tumors. MATERIAL AND METHODS: An immunohistochemical analysis for PGP 9.5 expression was carried out on all cases with the diagnosis of granular cell nerve sheath tumor seen over a 2-year period. In addition, we compared expression of PGP 9.5 with other accepted markers for neuroectodermal tumors including anti-S-100 protein and NKI/C3 monoclonal antibodies. RESULTS: Six granular cell nerve sheath tumors were diagnosed in over 80,000 dermatopathology specimens in the two-year period. These cases were all positive for PGP 9.5 as well as for S-100 protein and NK1/C3. CONCLUSION: These findings identify PGP 9.5 as a new immunohistochemical marker for use in the diagnosis of granular cell tumors. They also strengthen the histogenetic relationship between granular cell nerve sheath tumors and tumors of Schwann cell or perineurial origin.

Intra-epidermal and intra-dermal sebocrine adenoma with cystic degeneration and hemorrhage.

BACKGROUND: The ducts of eccrine glands may give rise to intra-epidermal, confluent epithelial and intra-dermal adenomas known as hidroacanthoma simplex, eccrine poroma, and dermal duct tumor, respectively. An apocrine and sebaceous counterpart of the eccrine poroma has been described by several authors as adnexal, poroma-like adenoma with apocrine and sebaceous differentiation or sebocrine adenoma. METHODS: Using clinical history and routine histologic techniques, we describe a new lesion with features similar to sebocrine adenoma but representing the intra-epidermal and intra-dermal counterparts with cystic degeneration and hemorrhage. Briefly, an 84-year-old female presented with a 6 mm dark tan papule on the neck that clinically appeared as an unusual macular seborrheic keratosis with underlying hemorrhage. RESULTS: Histopathological examination showed a benign dermal cystic appendage tumor with pale polygonal cells, occasional non-keratinizing ducts, sebaceous differentiation and central hemorrhage with fibrin deposits. Serial sections did not reveal any epidermal connection. However, epithelioid cells with large nuclei in an intra-epidermal pagetoid pattern were focally seen. CONCLUSION: These findings represent a new cystic, hemorrhagic variant of sebocrine adenoma.

Altered basic fibroblast growth factor expression in common epidermal neoplasms: examination with in situ hybridization and immunohistochemistry.

BACKGROUND: The fibroblast growth factor family consists of acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and Kaposi fibroblast growth factor (kFGF). The distribution of these growth factors in skin disease has not been determined. OBJECTIVE: The purpose of this study was to determine the distribution of these growth factors in keratinocytic lesions and normal skin. METHODS: Skin sections from common disorders of keratinocytes were examined by in situ hybridization with specific probes for aFGF, bFGF, and kFGF, and immunohistochemistry. RESULTS: Of the growth factors studied, only bFGF was present in skin. bFGF messenger RNA was highly expressed in both normal epidermis and benign and malignant epithelial neoplasms. In normal skin, bFGF was expressed predominantly in a suprabasal fashion, whereas in epithelial neoplasms, homogeneous high-level expression of bFGF was observed. CONCLUSION: bFGF is the primary member of the fibroblast growth factor expressed in the skin. The source of synthesis of bFGF is keratinocytes. Immunoreactivity for bFGF appears to be primarily confined to upper layers of the epidermis in normal skin, but is expressed at all layers of the epidermis in both benign and malignant neoplastic conditions. Genetic changes that promote epithelial tumors may also promote translation of bFGF messenger RNA into protein. Specific inhibition of bFGF activity may have application in the treatment of common skin diseases.

Role of cytoplasmic dynein in melanosome transport in human melanocytes.

Cytoplasmic dynein is a microtubule-associated retrograde-directed motor molecule for transport of membrane-bound organelles. To determine whether cytoplasmic dynein is expressed in melanocytes, we performed reverse transcriptase polymerase chain reaction using melanocyte cDNA and primers complementary to human brain cytoplasmic dynein heavy chain. A polymerase chain reaction product of the expected molecular size was generated and the identity was confirmed by sequence analysis. Western blotting of total melanocyte proteins reacted with an anti-intermediate chain cytoplasmic dynein antibody identified the appropriate 74 kDa band. To determine whether cytoplasmic dynein plays a role in melanosome transport, duplicate cultures were treated with cytoplasmic dynein antisense or sense (control) oligodeoxynucleotides and the cells were observed by high-resolution time-lapse microscopy, which allows visualization of melanosomal aggregates and individual melanosomes. Antisense-treated melanocytes demonstrated a strong anterograde transport of melanosomes from the cell body into the dendrites, whereas melanosome distribution was not affected in sense-treated melanocytes. To determine whether ultraviolet irradiation modifies cytoplasmic dynein expression, melanocyte cultures were exposed to increasing doses of solar-simulated irradiation, equivalent to a mild to moderate sunburn exposure for intact skin. Within 24 h, doses of 5 and 10 mJ per cm2 induced cytoplasmic dynein protein, whereas doses of 30 mJ per cm2 or more were associated with decreased levels of cytoplasmic dynein compared with sham-irradiated controls. Our data show that cytoplasmic dynein participates in retrograde melanosomal transport in human melanocytes and suggest that the altered melanosomal distribution in skin after sun exposure is due, at least in part, to decreased cytoplasmic dynein levels resulting in augmented anterograde transport.

Kinesin participates in melanosomal movement along melanocyte dendrites.

Movement of melanosomes along melanocyte dendrites is necessary for the transfer of melanin pigment from melanocytes to basal and suprabasal keratinocytes, an event critical to epidermal photoprotection and maintenance of normal skin color. Recent murine data suggest that in melanocyte dendrites the microtubule-associated melanosome movement is bidirectional and that actin-associated myosin V secures the peripheral melanosomes, preparing them to be transferred to surrounding keratinocytes. We now report that human melanocytes express high levels of kinesin, a molecule that participates in microtubule-associated transport of organelles in other cell types, and that ultrastructurally kinesin molecules are closely associated with melanosomes. To determine whether kinesin participates in melanosomal transport, cultured melanocytes were treated with sense or antisense oligonucleotides complementary to kinesin heavy chain sequences. Antisense oligonucleotides decreased kinesin protein levels and inhibited the bidirectional movement of the melanosomes, promoting their backward movement. Furthermore, guinea pigs were exposed to ultraviolet B irradiation, known to enhance transport of melanosomes from melanocytes to epidermal keratinocytes, and then were treated with kinesin sense or antisense oligonucleotides. The areas that were treated with kinesin antisense oligonucleotides showed significantly less pigmentation clinically and histologically than control (sense) oligonucleotide-treated areas. As observed ultrastructurally, in antisense-treated areas melanosomes remained in melanocyte dendrites but over several days were not transferred to the surrounding keratinocytes. Our study supports a major role for kinesin in microtubule-associated anterograde melanosomal transport in human melanocyte dendrites.

Zyxin redistributes without upregulation in migrating human keratinocytes during wound healing.

Cell migration, growth, and survival is modulated by focal adhesions linking extracellular matrix proteins, cell adhesion molecules, and the cytoskeleton. Zyxin is a focal adhesion phosphoprotein that shares homology with Listeria ActA protein in promoting actin filament assembly; it also has specialized protein-protein interface domains implicating an important role in cell growth and differentiation. We investigated the distribution of zyxin in normal and migrating human keratinocytes in wounds in vitro and in situ using confocal laser microscopy. Zyxin expression in high-density nonmigrating keratinocytes versus low-density migrating keratinocytes was determined by western immunoblotting and time lapse image analysis. In normal epidermis, zyxin exhibited a punctate staining pattern throughout the cytoplasm and was excluded from the intercellular spaces. In wounds, the punctate staining also localized in the edge of the migrating keratinocyte sheets; however, intercellular spaces were absent. Likewise, in vitro keratinocytes showed punctate staining throughout the cytoplasm. Migrating cultured keratinocytes next to wounds, however, had large focal contacts in the cell periphery where actin bundles converged at focal adhesions. Western immunoblots and confocal experiments with protein synthesis inhibition by cycloheximide confirmed that this difference in distribution of zyxin in migrating versus nonmigrating keratinocytes is due to the redistribution and not upregulation of zyxin. The abundance of zyxin and its relative change in distribution from normal to migrating keratinocytes in wounds is consistent with its role in cytoskeletal organization of actin bundles.

CD44 variant isoform CD44v10 expression of human melanoma cell lines is upregulated by hyaluronate and correlates with migration.

CD44, a multifunctional adhesion receptor involved in cell-cell and cell-matrix interactions, plays an important role in the local progression and metastasis of malignant tumours. We investigated relative CD44 variant isoform mRNA expression in six human melanoma cell lines and determined cell migration on hyaluronic acid (HA) coated substrates. Haematopoietic form (CD44H) mRNA expression increased in all melanoma cell lines after plating on HA, whereas the relative CD44 variant exon 10 (CD44v10) mRNA expression increased in only three of the cell lines. Cell migration rates increased on substrates coated with HA in the three CD44v10-positive cell lines, whereas the three CD44v10-negative cell lines showed no modification in migration rates. Immunofluorescent labelling of CD44v10 revealed increased expression with plaques localized to the periphery of cells. Cell lines with increased relative CD44v10 expression exhibited significantly higher mean migration rates on HA. These results indicate that CD44v10 expression functionally relates to melanoma cell migration and suggest that interaction between CD44v10 and HA plays a role in the variable tissue invasion and aggressiveness of different melanoma clones.

Treatment of benign and atypical nevi with the normal-mode ruby laser and the Q-switched ruby laser: clinical improvement but failure to completely eliminate nevomelanocytes.

OBJECTIVE: To evaluate the effect of normal-mode and Q-switched ruby laser light (694 nm) on nevomelanocytes of benign, atypical, and congenital nevi. DESIGN: Half of the lesion of each of 31 nevi was treated with either the Q-switched ruby laser or the normal-mode ruby laser or both; the other half of the lesion was covered with aluminum foil and was not treated. SETTING: A university-affiliated, hospital-based laser center. PATIENTS: Sixteen patients with a total of 31 melanocytic nevi were enrolled in the study. INTERVENTIONS: All nevi were evaluated by at least 2 dermatologists to assess the degree of clinical atypia. Photographs were taken before and immediately after treatment and at each follow-up visit. The digital imaging system was used to evaluate the number of melanocytes in a measured length of basement membrane zone. MAIN OUTCOME MEASURE: Three individual readings (number of melanocytes per unit length) were taken on both the control and treated halves and then compared to quantitate treatment effect. All analyses used averages from 3 measurements. A Student paired t test was used to compare the treated and untreated sides. RESULTS: Sixteen (52%) of the nevi showed a clinically visible decrease in pigment on the treatment side at the 4-week follow-up visit. CONCLUSION: No lesions had complete histologic removal of all nevomelanocytes. Therefore, 1 or 2 laser treatments are not sufficient to cause complete removal of a lesion either clinically or histologically.

Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.

BACKGROUND: 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. MATERIALS AND METHODS: We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. RESULTS: Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. CONCLUSIONS: We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON.

Pathologic parameters in the diagnosis and prognosis of primary cutaneous melanoma.

Significant progress has been made in the last 10 years on the identification of histologic parameters that are independent predictors of melanoma prognosis, immunohistochemical markers of cells of melanocytic origin and changes in adhesion molecules, cytoskeletal proteins, growth factor receptors, cell signaling, and nuclear proliferation proteins associated with tumor progression. Histologic criteria may never be completely sufficient to predict behavior accurately, because the fundamental change that renders a cell aggressive may not be morphologically reflected and may require immunohistochemical or other molecular markers to establish behavior. To date, it is humbling that no immunohistochemical or molecular marker provides a greater predictable value for aggressive behavior than does the simple calibrated ocular micrometer to measure tumor thickness. Nevertheless, development of multiple histologic parameters with the concept of nontumorigenic RGP and tumorigenic VGP provides a reliable statistical model to predict metastases. Fortunately, nontumorigenic RGP melanomas with greater than 75% regression are rare. Thus, individual patients with melanoma without regression and without the tumorigenic VGP can be given reasonable assurance of 100% survival. Nevertheless, this assurance is based on a statistical model with a finite population studied. Additional studies are needed to confirm this model, as well as more definitive markers to precisely predict outcome for those individuals with tumorigenic VGP melanoma.

In situ and in vitro expression of protein kinase C alpha in human melanocytes.

Protein kinase C (PKC) is a multigene family of at least 12 isoforms involved in the transduction of extracellular signals. We investigated whether PKC-alpha, a major isoform known to be relatively abundant in brain tissue, is increased in human melanocytes relative to keratinocytes in vitro and in situ. Immunohistochemical staining for PKC-alpha in frozen neonatal human foreskin exhibited intermittent 2-3 + staining along the basal cell layer consistent with melanocytes, and 0-1 + staining of keratinocytes (on a scale of 0-3). Microscopic densitometry of the intermittent cellular staining was at least 3-fold greater than that of adjacent keratinocyte cell cytoplasm. Sequential frozen sections revealed similar intermittent cell staining with PKC-alpha and Mel-5 (tyrosinase related protein-1), known to specifically react with melanocytes. Northern blot analysis with a specific cDNA probe for PKC-alpha showed strong PKC-alpha mRNA expression in cultured melanocytes, whereas PKC-alpha mRNA in cultured non-stratifying keratinocytes was expressed at low levels. Western blot analysis revealed a prominent PKC-alpha band at approximately 80 kDa in melanocytes as opposed to a weak band in keratinocytes. Densitometry of the northern and western blots revealed that melanocytes had at least 10-fold more PKC-alpha mRNA and approximately 6-fold more PKC-alpha protein expression than keratinocytes. Total PKC activity measured in vitro revealed that melanocytes had 5-fold more activity than keratinocytes. The marked difference in melanocyte and keratinocyte expression of PKC-alpha provides further evidence for cell type specificity in the balance of PKC-alpha expression and may implicate differential PKC isoform signaling pathways in neuro-ectodermally derived cells.

Curcumin is an in vivo inhibitor of angiogenesis.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition.

Characterization of interleukin-1 alpha-induced melanoma cell motility: inhibition by type I and type II receptor-blocking monoclonal antibodies.

Interleukin-1 alpha (IL-1 alpha) induces cell motility in a variety of benign cell types and in some but not all malignant cell lines in vitro. This study characterizes the IL-1 alpha-induced motility of an aggressive human melanoma cell line that expresses both type I and type II IL-1 receptors. We tested the effect of monoclonal antibodies including function-blocking moAbs against the type I and type II IL-1 receptors on melanoma cell motility to determine which receptor is involved in signal transduction of IL-1 alpha-induced melanoma cell motility. IL-1 alpha significantly increases MM-RU melanoma cell migration in a dose-dependent manner using modified Boyden chamber assays at concentrations 10 to 100 times less than concentrations that significantly inhibit cell growth. Computer-assisted time-lapse image analysis reveals that the motility is inhibited in a dose-dependent manner by neutralizing antibodies against IL-1 alpha. Function-blocking monoclonal antibodies against either type I or type II IL-1 receptors show a significant inhibition of cytokine-induced enhanced cell migration. When both the anti-IL-1 receptor antibodies are added together, the motility-response is completely blocked to control levels. Taken together the data indicate that the IL-1 alpha-induced motility of MM-RU melanoma cells is mediated through both type I and type II IL-1 receptors. The significant inhibition of motility by neutralizing IL-1 alpha or blocking either one or both of the IL-1 receptors indicates an integration of IL-1-induced signals in the induction of melanoma cell migration.

Treatment of small nevomelanocytic nevi with a Q-switched ruby laser.

BACKGROUND: Small nevomelanocytic nevi are common and some are of cosmetic concern. Conventional therapy may cause a scar or permanent hypopigmentation. OBJECTIVE: Our purpose was to determine whether selective photothermolysis of pigmented cells by Q-switched ruby laser treatment removes small nevomelanocytic nevi in a nonscarring fashion. METHODS: Twelve patients with 18 small nevomelanocytic nevi were treated with a Q-switched ruby laser (694 nm, 28 nsec) at fluences of 8 J/cm2. Biopsy specimens were obtained after treatment at varying time intervals. RESULTS: Twelve lesions (67%) showed a complete response and six lesions (33%) had a partial response. The only adverse sequela observed was mild fibrosis of the papillary dermis, without loss of papillary architecture. CONCLUSION: The Q-switched ruby laser is effective in removing small melanocytic nevi. However, some might recur depending on the depth of the nevomelanocytic nests.

Effects of thallium ion on cellular components of the skin.

Thallium salts have been employed by dermatologists to cause depilation, and dermatologic features are prominent in thallium overdose. These features include alopecia and follicular hyperkeratosis. Administration of thallium to pregnant animals results in limb deformities, similar to those seen after thalidomide embryopathy. These findings suggest that thallium may act on keratinocytes, melanocytes, and endothelial cells. We show that thallium exerts pleiotropic effects on proliferation, cell shape and motility of multiple cell types. These findings may help explain the clinical findings of thallotoxicosis.

Clinical and histological responses of congenital melanocytic nevi after single treatment with Q-switched lasers.

BACKGROUND: Laser irradiation of congenital melanocytic nevi is a controversial treatment. Recurrence of lesions after laser treatment appears to be the rule, and the effects of laser irradiation on cellular biological behavior and the possible mutagenic responses of nevomelanocytes that have received nonlethal doses of irradiation are still unclear. Without treatment, there is an increased potential for malignant degeneration over a life-time. The purpose of this study was to examine the effects of Q-switched lasers on congenital nevi and to explain the mechanism(s) behind the response of the nevi to laser treatment. Five congenital nevi were divided into 3 equal parts: 1 part was treated with the Q-switched ruby laser at a wavelength of 694 nm, 1 part was treated with the Q-switched neodymium: YAG laser at a wavelength of 1064 nm, and 1 part was left untreated to serve as control. At intervals ranging from 3 days to 3 months after laser irradiation, the lesions were excised and evaluated by routine staining. This clinical study was conducted entirely at the Massachusetts General Hospital Dermatology Laser Center, Boston, Mass. OBSERVATIONS: Both the superficial and the deep portions of the congenital melanocytic nevi were affected by the 2 lasers, as evidenced by macroscopic inspection as well as microscopic evaluation. However, the Q-switched laser treatment did not destroy all nevomelanocytes, particularly in the deeper, less pigmented portions of the lesions. CONCLUSIONS: Both the Q-switched ruby laser and the neodymium: YAG laser often removed only the superficial portion of the congenital melanocytic nevi. The Q-switched ruby laser (694 nm) appeared to be more effective in removing nevomelanocytes than the Q-switched neodymium: YAG laser (1064 nm).