George Lipkin

Castleman's tumor and erosive lichen planus: Coincidence or association?: Report of a case

The rare association of severe erosive lichen planus and Castlemans tumor is presented. Castlemans tumor, or giant lymph node hyperplasia, is a benign neoplasm resembling thymic tumors and is associated with several immunologic abnormalities. Lichen planus also is associated with immunologic defects. One hypothesis linking these two diseases is that lymphocytes may become sensitized to tumor antigens on the Castlemans tumor and attack cross-reacting structures in the skin and other stratified squamous mucosae to produce the clinical picture of lichen planus.

Contact inhibition of growth is restored to malignant melanocytes of man and mouse by a hamster protein.

Abstract Contact inhibition of growth, an in vitro property whose loss has been correlated with increasing tumorigenicity in vivo, is restored to hamster malignant melanocytes by a glycoprotein previously isolated from culture medium of a contact-inhibited hamster melanocytic cell line. Such growth inhibition is characterized by changes in cultures from a disoriented, multilayered, pleomorphic morphology to well oriented monolayers of fibroblast-like cells, with significant reduction in saturation densities. The present studies show that: 1. 1. The morphologic and growth inhibitory effects transcend species barriers, occurring also in malignant melanoma cell lines of human and murine origin. 2. 2. Arrest of growth occurs in the G1 (G0) phase of the cell cycle, as in the classical case of diploid fibroblasts. 3. 3. Cessation of growth is not due to depletion of essential constituents of the growth medium, but occurs only as cells approach confluence. The melanocyte contact inhibitory factor (MCIF) may be the prototype for a class of surface-associated proteins concerned with regulation of normal cell-cell interactions leading to feedback inhibition of growth.

Plasticity of the Cancer Cell: Implications for Epigenetic Control of Melanoma and Other Malignancies

Current treatments of many advanced malignancies, including melanoma, have failed to significantly reduce mortality rates, necessitating newer approaches. There is now abundant evidence that cancer cells, given the appropriate environmental and molecular context, are capable of remarkable plasticity, including complete reversal of the malignant phenotype. Such reprogramming involves both extrinsic and intrinsic factors and can occur via three routes: perturbations of extracellular matrix-cell receptor interactions, modulation of intracellular signaling pathways, and exploitation of epigenetic inheritance. Studies demonstrate the potential for producing dramatic changes in structural, biochemical, immunological, and functional properties of a broad spectrum of tumor cell types, including melanoma, leading to growth arrest, differentiation, senescence, or self destruction. Translating the promise inherent in tumor cell plasticity to the clinical arena remains a major challenge, but it is likely that a variety of epigenetic methods will play an increasingly important and effective role in the future control of malignant melanoma and other cancers.

Susceptibility to NK cell lysis is abolished in tumor cells by a factor which restores their contact inhibited growth.

It is well recognized that physical contact between natural killer (NK) cells and tumor targets is necessary for cell lyses. Therefore, any modulation of the tumor cell surface that alters intercellular contact could affect NK cell cytotoxicity. To examine this hypothesis, a contact inhibitory factor (CIF), which had been shown to restore contact inhibition of growth to several malignant cell lines was tested for its ability to render such cells immune to recognition by NK cells. When three NK‐sensitive melanoma and two NK‐sensitive colon carcinoma targets were cultured with CIF, they did not only change morphologically, but also showed a 70% to 95% reduction in their sensitivity to lysis by NK cells. In addition, K562 cells, which grow in suspension and do not permit a morphologic evaluation of the CIF effect, also became resistant to lysis by NK cells after culture with CIF. CIF did not reduce the viability nor the cytotoxicity of NK cells. GIF did not contain interferon nor did the GIF‐treated targets induce the production of interferon during the cytotoxicity assay. It is concluded that restoration of contact inhibition of growth and resistance to NK cell lysis are cell surface phenomena that may run in parallel.

Glycoprotein-containing factor that mediates contact inhibition of growth.

Normal cells in vitro characteristically exhibit a form of growth control that has been termed “contact inhibition of growth,” ’ “density-dependent inhibition of growth,’12 or “ t~poinhib i t ion .”~ Such benign cells limit their growth by cellular intcractions that depend on population density. On growing together to form confluent (and in some cases well-oriented) monolayers, they stop proliferating, even though the culture medium is still capable of supporting growth a t lower cell densities. The population level a t which such cells stop dividing under defined culture conditions has been termed the saturation density. Such arrest of growth occurs in the G , (Go) phase of the cell cycle and is associated with a marked decrease in the rate of synthesis of DNA, RNA, and protein, increased turnover of certain cell surface proteins, and early diminution of transport of hexose and phosphate. By contrast, malignant cells do not exhibit this type of growth control: under identical culture conditions, on reaching confluence, they continue to multiply to form multilayered, disoriented heaps of cells, with significantly higher saturation densities than are found in cultures or their benign counterparts. Even in such crowded cultures, considerable DNA synthesis may continue, and there is little decline in transport of either hexose or phosphate. The capacity for normal contact inhibition of growth, although by no means the only component of normal growth control in vitro, as shown by work on characterization of serum and density revertants,‘ nevertheless is significantly related to the malignant process in vivo. The relevance of contact inhibition of growth as a valid experimental model for the study of growth control rests on the observation that it is a property that occurs in vitro whose loss is closely correlated with malignancy in vivo. For example, among different strains of a malignant cell line, there is a direct correlation between the degree of loss or contact inhibition of growth (measured as increasing saturation densities of cultures) and ease of transplantability of tumors in v i ~ o . ~ I n contrast, increased contact inhibition of cell division in cultures is associated with decreased efficiency of tumor initiation in vivo. ’J We recently found that a contact-inhibited line of hamster melanocytes (FF) produces a diffusible factor that restores contact inhibition of growth t o hamster malignant m e l a n ~ c y t e s . ~ The possible presence of a growth inhibitor i n the contact-inhibited (FF) cultures was suggested by crossover experiments in which mixtures of conditioned media (CM) from contact-inhibited FF cultures and noncontact-inhibited RPMI I846 hamster melanoma cultures significantly suppressed growth of the RPMI 1846 but not FF cells. Qualitative comparison of

Biochemical studies of a protein which restores contact inhibition of growth to malignant melanocytes

Summary A factor prepared from conditioned medium of a contact-inhibited hamster melanocytic cell line (FF), and which restores the capacity for contact inhibition of growth to malignant melanocytes, is a glycoprotein of molecular weight about 160000 whose amino acid composition shows an acid-base ratio of 2.04. Although the melanocyte contact inhibitory factor (MCIF) is a constituent of both contact-inhibited (FF) and non-contact-inhibited (RPMI 1846) melanocytes, being present in a fraction which includes endoplasmic reticulum and plasma membrane, it is spontaneously released only into culture media of the contact-inhibited (FF) cells. Addition of MCIF to cultures of highly malignant hamster melanocytes (RPMI 1846) is followed by a rapid fall of intracellular cGMP and rise in cAMP. A protein with electrophoretic mobility identical with that of MCIF is present in conditioned culture media of other contact-inhibited cell lines including a human epidermal line and human and mouse fibroblasts, but is absent from media of hamster melanoma, and much reduced in cultures of SV40-transformed mouse fibroblasts. MCIF may be a widely distributed growth regulatory macromolecule concerned with facilitating cell-cell interactions required for the generation and/or reception of normal signals leading to cessation of growth.

Restoration of in vitro growth control to malignant cells.

A glycoprotein (molecular weight, ca. 160,000) from culture medium of contact‐inhibited hamster melanocytes restores contact inhibition of growth to malignant melanocytes of man, mouse, and hamsters, and also effectively inhibits growth in vitro of a broad spectrum of malignant and normal cell types of ectodermal, mesodermal and endodermal origins, including human colon carcinomas. The melanocyte contact inhibitory factor (MCIF) produces G1 growth arrest in malignant melanocytes; inhibition of all cell types is reversible, dose‐related, and nontoxic at concentrations below 200 μg/ml, but selectively lethal to malignant cells at higher concentrations. An electrophoretically identical protein is present in culture media of contact‐inhibited melanocytes, fibroblasts, and epidermal cells, but absent from those of colon carcinomas, HeLa cells and malignant melanomas. Nevertheless, an MCIF‐like band is present in whole cell homogenates of human colon carcinomas and hamster melanomas. MCIF may permit normal surface interactions required for feedback inhibition of growth.