Biomedical subjects

Steven T Pals

Publications and source records attributed to Steven T Pals.

23 records · Page 2Linked to original sources

PubMed2002

Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma.

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.

Cell Division↗

PubMed2002

In situ analysis of the variable heavy chain gene of an IgM/IgG-expressing follicular lymphoma: evidence for interfollicular trafficking of tumor cells.

It is generally assumed that follicular lymphomas (FL) not only morphologically resemble normal germinal centers but have retained some functional characteristics of their non-neoplastic counterparts as well. Recent IgV gene analyses on a panel of FLs however, strongly suggested that FLs do not retain the capacity of somatic hypermutation and are not being selected on basis of the quality of their mIgV regions. To extend these findings, we investigated the follicular organization and class switching in a FL that consisted of both IgM- and IgG-expressing tumor cells with a high somatic mutation load and significant intraclonal V(H) gene diversity. V(H)-C(mu) and V(H)-Cgamma gene transcripts were amplified and sequenced from samples of approximately 50 tumor cells, isolated from frozen tissue sections by laser microdissection. We identified many different subclones and obtained limited evidence of subclone dominance in individual follicles. Remarkably, several subclones were found scattered over different follicles. All samples contained IgM- and IgG-expressing tumor cells with, in general, non-identical mutation patterns, which is not in support of ongoing class switching. Accordingly, no switch circle recombination products were found. The findings indicate that the neoplastic follicles lack the organization and functions typical of reactive germinal centers.

Cell Movement↗

PubMed2002

CD44 is exposed to the extracellular matrix at invasive sites in basal cell carcinomas.

We have previously shown, by light microscopy, that the level of expression of CD44 (pan-CD44, CD44v3, CD44v5, and CD44v6) in human basal cell carcinomas is related to growth pattern and invasiveness (Br J Dermatol 1099;140:17-25). We have now studied the fine distribution of these CD44 isoforms in the same tumors using immunoelectron microscopy. Despite the strong differences in the level of expression in tumor areas with different growth patterns, CD44 was consistently found almost exclusively at intercellular surfaces, with a very strong predilection for widened intercellular pouches, ie, identical to the distribution in the normal epidermis. This prevalent distribution corroborates a role for CD44 in maintaining hyaluronan-filled spaces (J Histochem Cytochem 1998;46:241-248). However, the correlation between the presence of CD44 and the presence of such pouches was not absolute, indicating that other factors are involved as well. In contrast to the prevailing literature, we also found a weak but distinct labeling of cell surfaces facing the extracellular matrix. Interestingly, this appeared significantly elevated in the thinnest, most irregular, and usually most peripheral tumor cell strands, where it was associated with tumor cell protrusions and absence of a basal lamina. Thus, the CD44(+) protrusions were in direct contact with the extracellular matrix and apparently represented sites of invasion. The mechanisms that may contribute to a role of CD44 at these sites include binding of extracellular matrix components (notably hyaluronan) and several biologically active factors such as hepatocyte growth factor/scatter factor and matrix metalloproteinase 9.

Basal Cell Carcinoma↗

PubMed2002

Immune responsiveness in renal transplant recipients: mycophenolic acid severely depresses humoral immunity in vivo.

BACKGROUND: Current immunosuppressive drug treatments for renal transplant recipients result in high one-year graft survival rates. Despite adequate suppression of the immune response directed to the allograft, the immune system remains able to cope with many infectious agents. METHODS: To define the influence of distinct immunosuppressive treatment protocols, primary and secondary cellular and humoral immune responses in groups of renal transplant recipients were studied: patient treated with prednisolone and cyclosporine A (P/CsA); with IgA CD3 monoclonal antibody as a rejection treatment superimposed on prednisolone and cyclosporine A (IgA CD3 mAb+P/CsA); and with prednisolone, cyclosporine A and mycophenolate mofetil (P/CsA/MMF). RESULTS: Primary in vitro proliferative responses to the protein antigen keyhole limpet hemocyanin (KLH) were not significantly disturbed in P/CsA treated patients, or in IgA CD3 mAb+P/CsA and P/CsA/MMF treated patients. In vitro proliferative responses to the recall antigen tetanus toxoid (TT) were similarly unaffected. Antigen-specific antibody responses to immunization with KLH and TT were not affected by treatment with P/CsA, or by IgA CD3 mAb+P/CsA, but were severely disturbed in patients treated with P/CsA/MMF. All patients displayed a profound inhibition of the delayed-type hypersensitivity skin reactivity to KLH and recall antigens. Nevertheless, in most patients with P/CsA treatment, T cell infiltrates were observed in skin biopsies from the site of KLH challenge, while expression of intercellular cell adhesion molecule-1 (ICAM-1) expression in challenged skin was significantly decreased in these patients. The balance between T helper 1 and T helper 2 cells was unaffected by immunosuppressive treatments during one year of follow-up. CONCLUSIONS: Immunosuppressive drug treatment with P/CsA inhibits delayed-type hypersensitivity skin reactions to both primary and frequently encountered antigens. Histological studies indicate an effect on ICAM-1 expression, leaving the influx of CD3pos T cells unaffected. Administration of a 10-day course of IgA CD3 mAb does not add profound immunosuppressive effects on the measured parameters. In contrast, addition of treatment with MMF profoundly decreases both primary and secondary humoral immune responsiveness in vivo. Finally, no effect of the studied immunosuppressive drugs on Th1/Th2 balance in vivo was measured.

Adolescent↗

PubMed2002

CD44 expression in IgA nephropathy.

Immunoglobulin A (IgA) nephropathy is a frequent, chronic renal disease characterized by a broad spectrum of clinical presentations and pathologic findings. CD44, a family of type I transmembrane glycoproteins involved in cell-cell and cell-matrix interactions, may orchestrate partially the cascade of inflammation, accumulation of myofibroblasts, and fibrosis leading to end-stage renal disease. To clarify the possible role of CD44 in the progression of IgA nephropathy, the expression of CD44 in glomeruli and the tubulointerstitial compartment was analyzed in 25 renal biopsy specimens of patients with IgA nephropathy and was correlated to histopathologic, serologic, and urinary parameters. The expression of CD44 correlated significantly with the degree of glomerular and interstitial damage, even better than the accumulation of alpha-smooth muscle actin-positive myofibroblasts, which is recognized as a reliable marker for the progression of IgA nephropathy. A positive correlation also was found between proteinuria and the expression of CD44 in the tubulointerstitial compartment. The glomerular and tubulointerstitial expression of CD44 correlated with the degree of renal damage in IgA nephropathy and could be a reliable marker of the progression of IgA nephropathy. CD44 may have a pivotal role in the cascade of renal inflammation and fibrosis.

Adult↗