CD1c antigens are present in normal and neoplastic B-cells

The immunohistochemical detection of CD1c antigen is described in mantle zone B-cells of the tonsil, lymph node, and spleen, and also in the marginal zone B-cells of the spleen. CD1c expression was observed in most cases of low-grade, but in only a single case of high-grade, B-cell non-Hodgkin's lymphoma. It was not detected in germinal centre cells, nor in Epstein-Barr virus-transformed or Burkitt's lymphoma B-cell lines. This distribution suggests that CD1c expression may occur preferentially in slowly proliferating B-cell populations and does not support previous suggestions that CD1c is a human equivalent of the mouse thymus leukaemia antigens.     

Cytoenzymatical differentiation of normal and neoplastic plasma cells

A histochemical method is described of differentiating between normal and neoplastic cells in plasma using the activity of various enzymes characteristic of plasma cells. It was found that in both types of cell increased or diminished activity of cytoenzymes is a useful means of distinguishing between normal and abnormal cells.     

Dysregulation of CD30+ T cells by leukemia impairs isotype switching in normal B cells

Chronic lymphocytic leukemia (CLL) is associated with impaired immunoglobulin (Ig) class-switching from IgM to IgG and IgA, a defect that leads to recurrent infections. When activated in the presence of leukemic CLL B cells, T cells rapidly up-regulate CD30 through an OX40 ligand and interleukin 4 (IL-4)-dependent mechanism. These leukemia-induced CD30+ T cells inhibit CD40 ligand (CD40L)-mediated S mu-->S gamma and S mu-->S alpha class-switch DNA recombination (CSR) by engaging CD30 ligand (CD30L), a molecule that interferes with the assembly of the CD40-tumor necrosis factor receptor-associated factor (TRAF) complex in nonmalignant IgD+ B cells. In addition, engagement of T cell CD30 by CD30L on neoplastic CLL B cells down-regulates the CD3-induced expression of CD40L. These findings indicate that, in CLL, abnormal CD30-CD30L interaction impairs IgG and IgA production by interfering with the CD40-mediated differentiation of nonmalignant B cells.     

CD44 and the adhesion of neoplastic cells.

CD44 is a family of transmembrane glycoproteins that act mainly as a receptor for hyaluronan. It can also bind some other extracellular matrix ligands (chondroitin sulphate, heparan sulphate, fibronectin, serglycin, osteopontin) with lower affinity. CD44 is encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing. The standard, ubiquitously expressed isoform of CD44, does not contain sequences encoded by these variant exons. Numerous variant isoforms of CD44 containing different combinations of exons v1-v10 inserted into the extracellular domain can be expressed in proliferating epithelial cells and activated lymphocytes. CD44 plays a significant role in lymphocyte homing. Both alternative splicing and glycosylation influence receptor function of the molecule, usually reducing its affinity to hyaluronan. The cytoplasmic domain of CD44 communicates with the cytoskeleton via ankyrin and proteins belonging to the ezrin-moesin-radixin family. Relatively little is known about the intracellular events following interactions of CD44 with its ligands. Some variant isoforms, especially those containing sequences encoded by v6-v10, are overexpressed in both human and animal neoplasms. In a rat pancreatic adenocarcinoma model one of the variant CD44 isoforms was proved to be determinant in the metastatic process. For some human neoplasms (carcinomas of the digestive tract, non-Hodgkin's lymphomas, thyroid carcinomas, and others) correlations have been made between the particular pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumours, such as grade, stage, presence of metastases, and survival. In vitro studies indicate that modifications of CD44 expression result in different ligand recognition and influence cell motility, invasive properties, and metastatic potential of experimental tumours. Investigation of CD44 neoexpression can be useful both in early cancer diagnosis and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation.     

Analysis of mammosomatotropic cells in normal and neoplastic human pituitaries

The reverse hemolytic plaque assay (RHPA) was used to analyze hormone secretion in normal and neoplastic human pituitary cells. Immunocytochemical (ICC) staining for PRL and GH with the peroxidase method and ultrastructural ICC with colloidal gold labeling were used along with the RHPA to analyze for mammosomatotropic (MS) cells in these dissociated and cultured pituitary cells. MS cells were identified in both normal and neoplastic pituitary tissues. Quantitation of plaque areas, showed that PRL cells from normal pituitaries had significantly larger plaque areas than PRL cells from PRL-producing adenomas or from mixed PRL-GH producing adenomas.     

Immunoreactivity of normal and neoplastic human tissue mast cells

Immunoreactivity of human tissue mast cells (TMCs) was studied in one case of solitary mastocytoma of the skin, three cases of malignant mastocytosis, and in six lymph nodes with reactive intrasinusoidal increase of TMCs. Immunohistochemically, TMCs reacted positively to antisera against vimentin, common leukocyte antigen (CLA), lysozyme, alpha 1-antitrypsin (alpha 1-AT), and alpha 1-antichymotrypsin (alpha 1-ACT) and to a monoclonal antibody (KiB3) that detects preferentially B-lymphocytes. Additionally, strong positive reactions to polyclonal antisera against adrenocorticotropic hormone (ACTH) and human peptide histidine isoleucine (PHI) and weaker reactions to antisera against leu-enkephalin and met-enkephalin were observed; all other antisera tested yielded negative results. Positive stainings for vimentin, CLA, alpha 1-AT, alpha 1-ACT, and lysozyme further support the hypothesis that human TMCs may be related to the myeloid-monocytic system. The positive reactivity of TMCs to antisera against ACTH, PHI, leu-enkephalin, and met-enkephalin has not been reported previously. These findings suggest that TMCs are able to store and/or produce regulatory peptides in addition to many other well-known, granule-bound mediators.     

Surface morphology of normal and neoplastic rat cells.

Nontumorigenic rat cells and their tumorigenic counterparts were studied with scanning electron microscopy under controlled conditions in vitro and with transmission electron microscopy after replantation in vivo to discern if external morphology reflected the cell's neoplastic state or the etiology of transformation. Interphase cells in six of seven nontumorigenic lines were flat and monolayered under confluent conditions and exhibited smooth, nonactive cell surfaces. A nontumorigenic cell line morphologically transformed with human adenovirus-2 consisted of spherical cells with blebbed surfaces. Cells from six tumorigenic lines transformed with avian sarcoma virus had highly active surfaces with many surface projections. Cells from two chemical carcinogen-transformed rat embryo lines were flat with no surface projections in subconfluent culture and rounded with only a few microvilli at high densities, but cells from a sarcoma chemically induced in an adult rat were villous. When villous cells were syngeneically replanted in vivo, they lost most microvilli. The external morphology of cells was influenced by a number of factors simultaneously, with no universal pattern associated with tumorigenic capacity or transforming agent.     

Merkel cells, normal and neoplastic: an update

Merkel cells (MC) occur in the basal epidermal layer, hair follicles, and oral mucosa, as complexes with sensory axons. The axons transduce slowly adapting type I mechanoreception, and MC modulate their sensitivity. MC also determine and maintain the 3-dimensional epidermal structure. They have neuroendocrine granules, rigid spinous processes, and desmosomal junctions with each other and with keratinocytes. Rare MC are dermaWl. Current evidence supports a basal cell origin. Merkel cell carcinomas (MCC) occur mostly in sun-exposed skin in old age. Trabecular, intermediate, or small cell in pattern, MCC have neuroendocrine granules, intercellular junctions, rigid spinous processes, and a paranuclear collection of intermediate filaments staining for cytokeratin 20. Most MCC behave indolently, but those with the small cell pattern, and some with the intermediate pattern, are aggressive and rapidly fatal.     

Adhesion of normal and neoplastic lymphoid cells to fibroblasts

Adhesion between lymphocytes and other cells is critical to many processes in the normal immune system. Alteration in the expression of cell adhesion molecules may be important in determining the behaviour of malignant lymphomas. In this study, the adhesion of normal lymphocytes to fibroblasts is compared with the adhesion of the T-cell lymphomas J6 and Hut78 ICRF. J6 was significantly more adherent to fibroblasts than either Hut 78 or PBL despite the fact that J6 expresses almost no LFA-1. Anti-LFA-1 had little effect on the basal adhesion of Hut 78 ICRF or PBL. Addition of anti-CD2 caused enhanced adhesion of J6 and PBL but not Hut 78ICRF, which expresses little of this molecule. This enhancement was abrogated by anti-LFA-1. Anti-CD45 also caused enhanced adhesion of PBL. This was largely due to LFA-1-mediated homotypic cell adhesion. The tumour cell lines display no such homotypic adhesion and the small enhancement of fibroblast adhesion was much less affected by the anti-LFA-1 antibody. These results show the complex interactions which occur between adhesion molecules and that differences in patterns of expression between normal and neoplastic cells could be a major determinant of tumour cell behaviour.     

Differential effects of CD40 stimulation on normal and neoplastic cell growth

CD40 is a molecule in the tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family that is present on both normal and neoplastic B lineage cells. It is also expressed on carcinoma and melanoma cells and can be augmented with interferon gamma. CD40 stimulation in normal B cells has been demonstrated to promote normal B cell differentiation and growth in vitro. In contrast to these effects, CD40 stimulation by either anti-CD40 antibodies or a recombinant soluble CD40 ligand can inhibit the growth of human breast carcinomas and aggressive histology B lymphomas in vitro and in vivo. This is believed to occur by activation-induced cell death (AICD) in which stimuli that promote the growth of normal cell types inhibit the growth of neoplastic counterparts. This occurs through the induction of apoptosis, necrosis and/or cell cycle arrest. Thus, CD40 stimulation may be of potential clinical use in the treatment of carcinomas and B cell lymphomas. This review shall provide an overview of the various effects of CD40 stimulation on both normal and neoplastic cell types.     

Evaluation of normal and neoplastic human mast cells for expression of CD172a (SIRPalpha), CD47, and SHP-1

Signal regulatory proteins (SIRPs) and tyrosine phosphatases have recently been implicated in the control of receptor tyrosine kinase (RTK)-dependent cell growth. In systemic mastocytosis (SM), neoplastic cells are driven by the RTK KIT, which is mutated at codon 816 in most patients. We examined expression of SIRPalpha, SIRPalpha ligand CD47, and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), a tyrosine phosphatase-type, negative regulator of KIT-dependent signaling, in normal human lung mast cells (HLMC) and neoplastic MC obtained from nine patients with SM. As assessed by multicolor flow cytometry, normal LMC expressed SIRPalpha, CD47, and SHP-1. In patients with SM, MC also reacted with antibodies against SIRPalpha and CD47. By contrast, the levels of SHP-1 were low or undetectable in MC in most cases. Corresponding data were obtained from mRNA analysis. In fact, whereas SIRPalpha mRNA and CD47 mRNA were detected in all samples, the levels of SHP-1 mRNA varied among donors. To demonstrate adhesive functions for SIRPalpha and CD47 on neoplastic MC, an adhesion assay was applied using the MC leukemia cell line HMC-1, which was found to bind to immobilized extracellular domains of SIRPalpha1 (SIRPalpha1ex) and CD47 (CD47ex), and binding of these cells to CD47ex was inhibited by the CD172 antibody SE5A5. In summary, our data show that MC express functional SIRPalpha and CD47 in SM, whereas expression of SHP-1 varies among donors and is low compared with LMC. It is hypothesized that CD172 and CD47 contribute to MC clustering and that the "lack" of SHP-1 in MC may facilitate KIT-dependent signaling in a subgroup of patients.     

Argyrophil cells in normal, hyperplastic, and neoplastic endometrium.

Scanty argyrophil cells are present in a substantial proportion of normal endometria, particularly during the secretory stage of the cycle. Argyrophil cells are also present in the various types of hyperplastic endometria and are found in more than half of endometrial adenocarcinomas. In some endometrial neoplasms they are present in abundance, but tumours rich in such cells do not have any features suggestive of a carcinoid tumour and are morphologically identical to adenocarcinomas of similar grade which are devoid of argyrophil cells. Endometrial adenocarcinomas containing argyrophil cells tend to be well differentiated and tend not to invade deeply into the myometrium. It is suggested that Müllerian epithelial stem cells possess a potentiality for differentiation into APUD cells.     

Monoclonal antibody OPD4 detects neoplastic T cells but does not distinguish between CD4 and CD8 neoplastic T cells in paraffin tissue sections.

Monoclonal antibody (MoAb) OPD4, reported to preferentially react with benign CD4 T cells in formalin-fixed tissue sections, was examined for its reactivity with 56 T-cell neoplasms after formalin or Bouin's fixation to determine if it also preferentially detects neoplastic CD4 T cells in paraffin tissue sections. Monoclonal antibody OPD4 did not preferentially detect neoplastic CD4 T cells, since it reacted with 22 of 38 (58%) CD4-positive compared with nine of 14 (64%) CD4-negative T-cell neoplasms. However, MoAb OPD4 appears to detect neoplastic T cells in Bouin's-fixed (11 of 20 cases [55%]) about as well as in formalin-fixed (20 of 32 cases [63%]) tissues. Since MoAb OPD4 does not preferentially react with neoplastic CD4 T cells, the utility of this MoAb as a pan-T-cell marker in routinely processed tissues was also explored and compared with that of Leu-22, UCHL-1, and CD3. All four antibodies reacted with approximately the same percentage of T-cell malignancies (51% to 57%). However, examination of different clinicopathologic groups and types of fixative highlighted differences. Monoclonal antibodies OPD4 and Leu-22 reacted with 62%, while CD3 detected only 41% of formalin-fixed, postthymic T-cell neoplasms. OPD4, UCHL-1, and CD3 each reacted with 55%, but Leu-22 recognized only 45% of Bouin's-fixed, postthymic T-cell malignancies. OPD4 reacted with none, but CD3 reacted with all four T-cell lymphoblastic lymphomas. Various antibody combinations were examined to determine an optimal panel for the recognition of T-cell neoplasms in paraffin sections. The combination of MoAbs OPD4 and Leu-22 detected 86% of postthymic T-cell neoplasms in formalin-fixed tissue sections. Furthermore, MoAb OPD4 appears to be relatively specific for T-cell neoplasms, detecting 31 of 56 (55%) T-cell malignancies, while only reacting with two of 39 (5%) B-cell neoplasms. Therefore, while not preferentially reactive with neoplastic CD4 T cells, MoAb OPD4 may be useful as a pan-T-cell marker of postthymic T-cell neoplasms in routinely processed, formalin-fixed tissues, especially when used in conjunction with MoAb Leu-22.     

Immunocytochemical analysis of MNDA in tissue sections and sorted normal bone marrow cells documents expression only in maturing normal and neoplastic myelomonocytic cells and a subset of normal and neoplastic B lymphocytes.

The human myeloid cell nuclear differentiation antigen (MNDA) is a nuclear antigen known to be expressed in mature myelomonocytic cell lines. An extensive immunocytochemical evaluation of fixed tissues confirmed MNDA expression in normal maturing granulocytes and monocytes and in acute nonlymphocytic leukemias and chronic myelogenous leukemia. MNDA was not detected in normal tissue histiocytes but was found in activated macrophages and foreign body giant cells associated with inflammation. Flow cytometric cell sorting of normal bone marrow established that MNDA is initially expressed in myeloid blast cells. Examination of lymphoid tissues showed a low level of expression in a population of normal mande B lymphocytes but not in germinal center cells or plasma cells. A subset of B cell neoplasms expressing MNDA included hairy cell leukemia, parafollicular (monocytoid) B cell lymphoma, mantle cell lymphoma, and small lymphocytic lymphoma. Cell sorting of normal bone marrow showed MNDA expression in CD20+/CD10-/CD5- B cells. MNDA was not detected in other normal bone marrow or all other nonhematopoietic cells. The hematopoietic cell-specific pattern of MNDA expression was elucidated through a comprehensive analysis of normal and neoplastic tissues, and the results provide further evidence of the coexpression of B- and myeloid cell markers in neoplastic B cells and identify a normal B cell population that might be related to the cell of origin of a subset of B cell neoplasms.