Byers Hr

Role of alpha 3 beta 1 and alpha 2 beta 1 integrins in melanoma cell migration.

Recent findings Indicate that variable expression of β Integrins may play a role In differential melanoma cell motility. Primary melanoma (PM) and metastatic melanoma (MM) cultures, derived from the same patient, were tested for their β1, α2, α3, and α6, Integrln subunlt expression and cell migration on type IV collagen (CN IV) or lamlnln (LN). The MM cell line expressed markedly Increased levels of the β1, α2 and α3, but not α6 subunlt compared to the PM cell line. The MM cell migration rate was significantly higher than that of the PM cell line on LN- or CN IV-coated substrates. Furthermore, the cell migration rate of both lines was significantly higher (p < 0.001) on these substrates than on the control substrates. The MM and PM cell migration was significantly Inhibited by function-blocking antl-β1 and anti-α3 MAbs, but not by the antl-α6 MAb tested. In contrast, the anti-α2 MAb significantly Inhibited MM but not PM cell migration. These data show that the α3 subunlt plays a significant role in melanoma cell motility on CN IV and LN and that. the α3 subunlt has a significant contribution to the motility of the MM cell line.

Increased diagnosis of thin superficial spreading melanomas: A 20-year study

BACKGROUND Diagnostic practice by dermatopathologists evaluating pigmented lesions may have evolved over time. OBJECTIVES We sought to investigate diagnostic drift among a group of dermatopathologists asked to re-evaluate cases initially diagnosed 20 years ago. METHODS Twenty nine cases of dysplastic nevi with severe atypia and 11 cases of thin radial growth-phase melanoma from 1988 through 1990 were retrieved from the pathology files of the Massachusetts General Hospital. All dermatopathologists who had rendered an original diagnosis for any of the 40 slides and the current faculty in the Massachusetts General Hospital Dermatopathology Unit were invited to evaluate the slide set in 2008 through 2009. RESULTS The mean number of melanoma diagnoses by the 9 study participants was 18, an increase from the original 11 melanoma diagnoses. A majority agreed with the original diagnosis of melanoma in all 11 cases. In contrast, a majority of current raters diagnosed melanoma in 4 of the 29 cases originally reported as dysplastic nevus with severe atypia. Interrater agreement over time was excellent (kappa 0.88) and fair (kappa 0.47) for cases originally diagnosed as melanoma and severely atypical dysplastic nevus, respectively. LIMITATIONS The unbalanced composition of the slide set, lack of access to clinical or demographic information, access to only one diagnostic slide, and imposed dichotomous categorization of tumors were limitations. CONCLUSIONS A selected cohort of dermatopathologists demonstrated a general trend toward the reclassification of prior nonmalignant diagnoses of severely atypical dysplastic nevi as malignant but did not tend to revise prior diagnoses of cutaneous melanoma as benign.

Integrin Expression in Malignant Melanoma and Their Role in Cell Attachment and Migration on Extracellular Matrix Proteins

The interaction between melanoma cells and extracellular matrix (ECM) components may be important for invasion and metastasis. The integrins belong to a family of protein heterodimers composed of α and β subunits and the β1‐integrins are especially important as ECM receptors.

Image analysis of Stage 1 melanoma (1.00–2.50 mm): lymphocytic infiltrates related to metastasis and survival

Image analysis of histologic sections of II patients with clinical Stage 1 melanoma, 1.00 mm – 2.50 mm, who developed metastasis, was done to determine the significance of lymphocytic infiltrates relative to metastasis and survival. An ago, sex, site, and thickness matched control group of non‐metastasizing clinical Stage 1 melanoma revealed no significant difference in the lymphocytic infiltrate parameters from the metastasizing group with the exception of the ratio of lymphocyte infiltrate width lo the tumor width (p = 0.003). Increased lymphocytic infiltrates within the tumor and subjacent lo its base significantly correlated with delayed lime to metastasis (p = 0.014 and p < 0.001, respectively) and longer survival period (p = 0.045 and p < 0.001, respectively). Lymphocytic infiltrate area at the tumor base in relation to tumor area was of prognostic value: the larger the ratio, the greater the time interval from metastasis to death (p = 0.008).

Actin Organization and Cell Migration of Melanoma Cells Relate to Differential Expression of Integrins and Actin-associated Proteins

We have recently described marked differences in cell migration rates and organization of actin in human melanoma cell lines isolated from various stages of tumor progression. Metastatic lines derived from lymph node metastases organized actin into stress fiber arrays and had high mean migration rates in vitro when compared to lines from other stages. Melanoma cells also reveal marked differences in localization of alpha‐actinin and β1 integrins at stress fiber termination sites (focal contacts). Disruption of this organization is induced by antibodies against β1 integrins. α‐actinin, recently postulated as having a role in linkage of actin to β1 integrins, is differentially expressed in melanoma cells by Northern blot analysis and a relatively high α‐actinin to actin ratio is associated with stress fiber formation and increased cell migration. Furthermore, actin‐binding protein, which cross‐links actin filaments, is also significantly increased in lines exhibiting high migration rates.

Differential effect of magnesium and calcium on integrin-mediated melanoma cell migration on type IV collagen and fibronectin.

We characterized the effects of extracellular Mg3+ and Ca2+ on the regulation of integrin-mediated cell migration of melanoma cells on type IV collagen and fibronectin. Melanoma cell motllity was studied using transmembrane migration in modified Boyden chambers and time-lapse video image analysis. Increasing Mg2+ or Ca2+ ion concentration from 0.1 to 10 mM produces distinct effects on melanoma cell migration on type IV collagen. Increasing Mg2+ ion concentration increased cell migration to a maximum at 5 mM, followed by a decrease at 10 mM. In contrast, Ca2+ alone did not support cell migration on this substrate. Combinations of both cations indicate that Ca2+ decreases cell migration in the presence of Mg2+. However, as opposed to the findings on collagen, peak migration on fibronectin was observed at 1 mM and Ca2+ alone was able to support migration on fibronectin. The Mg2+-enhanced migration was inhibited by function-blocking monoclonal antibodies anti-α2 or anti-β1 integrin subunit on the type IV collagen and anti-α5 and anti-β1, on fibronectin. Taken together, the data indicate that Mg2+ promotes the integrin-mediated cell migration, whereas Ca2+ has the opposite effect. The Ca2+ and Mg2+ concentration in the tumour extracellular microenvironment may modulate integrin-mediated functions and melanoma metastasis.

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

Interleukin-1α (IL-1α) 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-1α-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-1α-induced melanoma cell motility. IL-1α 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-1α. 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-1α-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-1α 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.