Markers of Cell Proliferation and Expression of Melanosomal Antigen in Lymphangioleiomyomatosis

Abstract

Pulmonary lymphangioleiomyomatosis (LAM), a disease of young women, is characterized by proliferation of immature-appearing smooth-muscle cells (LAM cells) in the lungs and abdomen. LAM cells react with monoclonal antibody HMB45, which recognizes a 100-kD glycoprotein (gp100) originally found in human melanoma cells. We investigated the expression and the subcellular localization of gp100 in lung tissue from patients with LAM and in human melanoma cell lines (Malme-3M, A2058, and CHL-1), and the relationship between this expression and cellular proliferation. Binding sites for HMB45 antibody in melanoma and LAM cells were located in cytoplasmic granules resembling immature melanosomes. LAM cells reactive for proliferating-cell nuclear antigen (PCNA), a marker of cellular proliferation, were spindle-shaped, in contrast to the large, epithelioid cells reacting with HMB45 antibody. In accord with this finding, we observed an inverse relationship between the immunostaining for HMB45 antibody and PCNA in LAM and melanoma cells. Thus, LAM and melanoma cells are heterogeneous with respect to their stages of proliferation and their expression of melanoma antigens. PCNA-positive cells, which are more likely to be negative for reactivity with HMB45 antibody, may be more relevant to the progression of LAM than are HMB45-positive cells, which are the hallmark of LAM.

Leiomyomatosis-Like Lymphangioleiomyomatosis of the Colon in a Female with Tuberous Sclerosis

“…Interestingly, positive HMB45 staining in colonic leiomyomatosis-like LAM and renal AML in our case is confined to the epithelioid cells, whereas the spindle cells are HMB45 negative, a feature akin to the HMB45 staining characteristic in the epithelioid and spindle cells of pulmonary LAM described by Matsumoto et al (21). These features implicate a close relationship between colonic leiomyomatosis-like LAM, pulmonary LAM, and AML.…”

“…First, there are clinical and histologic similarities between the smooth muscle proliferation of the colon in our case and that seen in pulmonary LAM (20,21), viz. the occurrence in a female of reproductive age with TSC and the histologic spectrum of changes that embody spindle and epithelioid smooth muscle cells surrounding endothelial-lined spaces in conjunction with a lymphangiomatous component and HMB45 expression.…”

Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

“…Morphologically LAMD-SM cells were spindle-like with high levels of basal DNA synthesis (see "Results"), and they showed positive immunoreactivity to anti-smooth muscle ␣-actin antibody (data not shown) and tuberin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) (See "Results"). However, LAMD-SM cells showed no immunoreactivity for HMB-45 (DAKO Co., Carpinteria, CA) (data not shown), which showed positive immunostaining of the epithelioid cells in LAM nodules (data not shown) (3,4,32) and in human melanoma, used as a positive control. All assays were performed on cells maintained for 48 h in serum-free DF basal media containing 1% bovine serum albumin before starting the experiment.…”

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

“…Marker proteins described to date, such as ␣-smooth muscle actin, vimentin, and desmin, are not unique to LAM cells, and specific cell-surface markers have not been reported. LAM cells do differ from normal smooth muscle cells by the presence of gp100, a 100-kDa glycoprotein found in melanoma that reacts with a monoclonal antibody, HMB45 (13), but percentages of HMB45-positive LAM cells varied from 17% to 67% in biopsies (2), with an inverse relationship between percentages of cells positive for proliferating cell nuclear antigen and HMB45 positivity (14). We therefore decided on genotype as a criterion for identification of LAM cells.…”