Regulation of growth and dissemination of a human lymphoma by CD44 splice variants

1995 ◽  
Vol 108 (4) ◽  
pp. 1723-1733 ◽  
Author(s):  
A. Bartolazzi ◽  
D. Jackson ◽  
K. Bennett ◽  
A. Aruffo ◽  
R. Dickinson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Growth ◽  
Splice Variants ◽  
Tumor Formation ◽  
Surface Glycoprotein ◽  
Cell Surface Receptor ◽  
Cell Surface Glycoprotein ◽  
Cd44 Isoforms ◽  
Coated Surfaces

CD44 is a polymorphic cell surface glycoprotein, currently proposed to be the principal cell surface receptor for hyaluronan. However, different isoforms of CD44, expressed in human lymphoid tumor cells, appear to have distinct effects on the ability of the cells to attach to hyaluronan-coated surfaces and on their capacity to form tumors in vivo. In the present study, we address the mechanisms that may regulate CD44 isoform-dependent adhesion to hyaluronan. We use a human Burkitt lymphoma, stably transfected with six different alternatively spliced human CD44 isoforms, to determine their potential hyaluronan binding and tumor growth promoting roles. We show that transfectants expressing CD44 splice variants that contain variable exons 6–10, 7–10 and 8–10 adhere to hyaluronan-coated surfaces weakly and that corresponding tumor formation in vivo is delayed with respect to CD44-negative parental cell-derived tumors. Abundant shedding of these three isoforms may play a significant role in determining the rate of tumor development. Transfectants expressing variable exon 3, on the other hand, fail to display CD44-mediated adhesion to hyaluronan, but form bone marrow tumors rapidly following intravenous injection. These observations suggest that different mechanisms regulate CD44-mediated adhesion and tumor growth, and provide evidence that expression of exon v3 may confer novel ligand-binding properties.

scholarly journals Distinct effects of two CD44 isoforms on tumor growth in vivo.

1991 ◽  
Vol 174 (4) ◽  
pp. 859-866 ◽  
Author(s):  
M S Sy ◽  
Y J Guo ◽  
I Stamenkovic
Keyword(s):  
Tumor Growth ◽  
B Cell Lymphoma ◽  
Metastatic Tumor ◽  
Tumor Formation ◽  
Surface Glycoprotein ◽  
Cdna Clones ◽  
Lymphoma Cells ◽  
Cell Surface Glycoprotein ◽  
Cd44 Isoforms

Tumor growth is dependent in part on interactions between tumor cells and the extracellular matrix of host tissues. Expression of the cell surface glycoprotein CD44/Pgp-1, which mediates cell-substrate interactions is increased in many types of malignancies, but the role of CD44 in tumor growth is largely undefined. Recently, two isoforms of CD44 have been identified: an 80-90 kD form, which has high affinity for cell bound hyaluronate and a 150 kD form which does not mediate attachment to hyaluronate-coated surfaces. In this work, human B cell lymphoma cells stably transfected with cDNA clones encoding either of the two CD44 isoforms were compared for tumorigenicity and metastatic potential in nude mice. Expression of the 80-90 kD form but not the 150 kD form of CD44 greatly enhanced both local tumor formation and metastatic proclivity of the lymphoma cells. Our results suggest that CD44 polypeptides may play an important role in regulating primary and metastatic tumor development in vivo.

scholarly journals Cellular tumorigenicity in nude mice. Test of associations among loss of cell-surface fibronectin, anchorage independence, and tumor-forming ability.

1979 ◽  
Vol 82 (1) ◽  
pp. 1-16 ◽  
Author(s):  
P Kahn ◽  
S I Shin
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Nude Mice ◽  
Diploid Cell ◽  
Tumor Formation ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Chicken Cell

Fibronectin (FN; also called large external transformation-sensitive [LETS] protein or cell-surface protein [CSP]) is a large cell-surface glycoprotein that is frequently observed to be either absent or greatly reduced on the surfaces of malignant cells grown in vitro. Because FN may be a useful molecular marker of cellular malignancy, we have carried out an extensive screening to test the specific association among the degree of expression of FN, anchorage-independent growth, and tumorigenicity in the athymic nude mouse. A variety of diploid cell strains and established cell lines were tested for the expression of surface FN by indirect immunofluorescence using rabbit antisera against human cold insoluble globulin, rodent plasma FN, or chicken cell-surface FN. Concomitantly, the cells were assayed for tumor formation in nude mice and for the ability to form colonies in methylcellulose. Tumorigenic cells often showed very low surface fluorescence, confirming earlier reports. However, many highly tumorigenic fibroblast lines from several species stained strongly with all three antisera. In contrast, the anchorage-independent phenotype was nearly always associated with tumorigenicity in approximately 35 cell lines examined in this study. In another series of experiments, FN-positive but anchorage-independent cells were grown as tumors in nude mice and then reintroduced into culture. In five of the six tumor-derived cell lines, cell-surface FN was not significantly reduced; one such cell line showed very little surface FN. Our data thus indicate that the loss of cell-surface FN is not a necessary step in the process of malignant transformation and that the growth of FN-positive cells as tumors does not require a prior selection in vivo for FN-negative subpopulations.

scholarly journals Differentiation-associated changes in CD44 isoform expression during normal hematopoiesis and their alteration in chronic myeloid leukemia

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2976-2985 ◽  
Author(s):  
S Ghaffari ◽  
GJ Dougherty ◽  
PM Lansdorp ◽  
AC Eaves ◽  
CJ Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Surface Glycoprotein ◽  
Pcr Analysis ◽  
Cell Surface Glycoprotein ◽  
Cd44 Isoforms ◽  
Cd44 Expression ◽  
Light Density ◽  
Very High

CD44 is a widely expressed, multifunctional, cell-surface glycoprotein that has been implicated in the regulation of normal hematopoiesis. In addition, expression of particular isoforms of CD44 has been associated with malignant transformation and/or the acquisition of metastatic potential. In this study, we used two recently developed monoclonal anti-CD44 antibodies, one reactive with an epitope shared by many CD44 isoforms and the other with an epitope unique to CD44 isoforms containing amino acids encoded by the alternatively spliced exon v10, to compare the expression of CD44 on primitive hematopoietic cells from the marrow of normal individuals and their neoplastic counterparts present in the peripheral blood of patients with chronic myeloid leukemia (CML). Multiparameter fluorescence-activated cell sorter (FACS) analysis and cell sorting studies showed that CD44 is normally expressed at high to very high levels on both long-term culture-initiating cells (LTC-IC) and granulopoietic colony-forming cells (granulocyte-macrophage colony-forming units [CFU-GM]). In contrast, primitive erythropoietic progenitors (burst-forming units-erythroid [BFU-E]) in normal marrow were more homogeneous in their expression of CD44, and very few (less than 5%) showed the very high levels of CD44 seen on 20% to 25% of LTC-IC and CFU-GM. Antibody staining showed the expression of exon v10-containing CD44 isoforms to be restricted to a small subpopulation (4% to 8%) of morphologically recognizable mature (CD34-) myeloid cells within the light-density fraction of normal marrow cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed the presence of two exon v10-containing mRNA species. In CML, a significantly greater proportion of the circulating neoplastic CFU-GM expressed very high levels of CD44, and these CFU-GM were accompanied by an increased number of light density v10+ cells, including some that coexpressed CD34. Nonmalignant hematopoietic progenitors mobilized by prior chemotherapy and growth factor treatment of patients with Hodgkin's disease or acute myeloid leukemia in remission showed no changes in CD44 expression relative to normal marrow progenitors. These results provide evidence of early differentiation-associated changes in CD44 expression during normal hematopoiesis in vivo that may be deregulated in the neoplastic clone of patients with CML.

scholarly journals Galectin–glycan lattices regulate cell-surface glycoprotein organization and signalling

2008 ◽  
Vol 36 (6) ◽  
pp. 1472-1477 ◽  
Author(s):  
Omai B. Garner ◽  
Linda G. Baum
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Targeted Delivery ◽  
Cell Types ◽  
Surface Glycoprotein ◽  
Membrane Domains ◽  
Cellular Functions ◽  
Cell Surface Glycoprotein

The formation of multivalent complexes of soluble galectins with glycoprotein receptors on the plasma membrane helps to organize glycoprotein assemblies on the surface of the cell. In some cell types, this formation of galectin–glycan lattices or scaffolds is critical for organizing plasma membrane domains, such as lipid rafts, or for targeted delivery of glycoproteins to the apical or basolateral surface. Galectin–glycan lattice formation is also involved in regulating the signalling threshold of some cell-surface glycoproteins, including T-cell receptors and growth factor receptors. Finally, galectin–glycan lattices can determine receptor residency time by inhibiting endocytosis of glycoprotein receptors from the cell surface, thus modulating the magnitude or duration of signalling from the cell surface. This paper reviews recent evidence in vitro and in vivo for critical physiological and cellular functions that are regulated by galectin–glycoprotein interactions.

scholarly journals CD44H regulates tumor cell migration on hyaluronate-coated substrate.

1992 ◽  
Vol 118 (4) ◽  
pp. 971-977 ◽  
Author(s):  
L Thomas ◽  
H R Byers ◽  
J Vink ◽  
I Stamenkovic
Keyword(s):  
Cell Migration ◽  
Cell Surface ◽  
Binding Capacity ◽  
Surface Glycoprotein ◽  
Cell Surface Receptor ◽  
Cell Surface Glycoprotein ◽  
Tumor Cell Migration ◽  
Coated Substrate ◽  
Direct Demonstration ◽  
Surface Receptor

CD44 is a broadly distributed cell surface glycoprotein expressed in different isoforms in various tissues and cell lines. One of two recently characterized human isoforms, CD44H, is a cell surface receptor for hyaluronate, suggesting a role in the regulation of cell-cell and cell-substrate interactions as well as of cell migration. While CD44H has been shown to mediate cell adhesion, direct demonstration that CD44H expression promotes cell motility has been lacking. In this work we show that a human melanoma cell line, stably transfected with CD44H, displays enhanced motility on hyaluronate-coated surfaces while transfectants expressing an isoform that does not bind hyaluronate, CD44E, fail to do so. Migration of CD44H-expressing transfectants is observed to be blocked by a soluble CD44-immunoglobulin fusion protein as well as by anti-CD44 antibody, and to depend on the presence of the cytoplasmic domain of CD44. However, cells expressing CD44H cytoplasmic deletion mutants retain significant binding capacity to hyaluronate-coated substrate. Taken together, our results provide direct evidence that CD44H plays a major role in regulating cell migration on hyaluronate-coated substrate.

scholarly journals Positive Feedback Regulation Between Adiponectin and T-Cadherin Impacts Adiponectin Levels in Tissue and Plasma of Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 934-946 ◽  
Author(s):  
Keisuke Matsuda ◽  
Yuya Fujishima ◽  
Norikazu Maeda ◽  
Takuya Mori ◽  
Ayumu Hirata ◽  
...  
Keyword(s):  
Cell Surface ◽  
Phospholipase C ◽  
Positive Feedback ◽  
Cardiac Tissue ◽  
Feedback Regulation ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Cleavage Enzyme ◽  
In Vivo Administration

Abstract Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.

scholarly journals The human alpha 2-macroglobulin receptor: identification of a 420-kD cell surface glycoprotein specific for the activated conformation of alpha 2-macroglobulin.

1990 ◽  
Vol 110 (4) ◽  
pp. 1041-1048 ◽  
Author(s):  
J D Ashcom ◽  
S E Tiller ◽  
K Dickerson ◽  
J L Cravens ◽  
W S Argraves ◽  
...  
Keyword(s):  
Cell Surface ◽  
Affinity Chromatography ◽  
Anion Exchange Chromatography ◽  
Binding Activity ◽  
Exchange Chromatography ◽  
Surface Glycoprotein ◽  
Cell Surface Receptor ◽  
Affinity Matrix ◽  
Cell Surface Glycoprotein ◽  
A Cell

Ligand affinity chromatography was used to purify a cell surface alpha 2-macroglobulin (alpha 2M) receptor. Detergent extracts of human placenta were applied to an affinity matrix consisting of alpha 2M, previously reacted with methylamine, coupled to Sepharose. Elution with EDTA specifically released polypeptides with apparent molecular masses of 420 and 39 kD. In some preparations, small amounts of a 90-kD polypeptide were observed. The 420- and 39-kD polypeptides appear specific for the forms of alpha 2M activated by reaction with proteinases or methylamine and do not bind to an affinity matrix consisting of native alpha 2M coupled to Sepharose. Separation of these two polypeptides was accomplished by anion exchange chromatography, and binding activity was exclusively associated with the 420-kD polypeptide. The purified 420-kD protein binds to the conformationally altered forms of alpha 2M that are known to specifically interact with alpha 2M receptors and does not bind to native alpha 2M. Binding of the 420-kD polypeptide to immobilized wheat germ agglutinin indicates that this polypeptide is a glycoprotein. The cell surface localization of the 420-kD glycoprotein was confirmed by affinity chromatography of extracts from surface radioiodinated fibroblasts. These properties suggest that the 420-kD polypeptide is a cell surface receptor for the activated forms of alpha 2M.

Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1–deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 1114-1123 ◽  
Author(s):  
Xu-Ming Dai ◽  
Xiao-Hua Zong ◽  
Vonetta Sylvestre ◽  
E. Richard Stanley
Keyword(s):  
Cell Surface ◽  
Biologically Active ◽  
Surface Glycoprotein ◽  
Long Bone ◽  
Kidney Cortex ◽  
Colony Stimulating Factor ◽  
Cell Surface Glycoprotein ◽  
Transgenic Expression ◽  
Stimulating Factor

AbstractThe primary macrophage growth factor, colony-stimulating factor 1 (CSF-1), is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell surface glycoprotein (csCSF-1). To investigate the in vivo roles of csCSF-1, we created mice that exclusively express csCSF-1, in a normal tissue-specific and developmental manner, by transgenic expression of csCSF-1 in the CSF-1-deficient osteopetrotic (Csf1op/Csf1op) background. The gross defects of Csf1op/Csf1op mice, including growth retardation, failure of tooth eruption, and abnormal male and female reproductive functions were corrected. Macrophage densities in perinatal liver, bladder, sublinguinal salivary gland, kidney cortex, dermis, and synovial membrane were completely restored, whereas only partial or no restoration was achieved in adult liver, adrenal gland, kidney medulla, spleen, peritoneal cavity, and intestine. Residual osteopetrosis, significantly delayed trabecular bone resorption in the subepiphyseal region of the long bone, and incomplete correction of the hematologic abnormalities in the peripheral blood, bone marrow, and spleens of CSF-1-deficient mice were also found in mice exclusively expressing csCSF-1. These data suggest that although csCSF-1 alone is able to normalize several aspects of development in Csf1op/Csf1op mice, it cannot fully restore in vivo CSF-1 function, which requires the presence of the secreted glycoprotein and/or proteoglycan forms. (Blood. 2004;103:1114-1123)

scholarly journals Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development.

1994 ◽  
Vol 180 (1) ◽  
pp. 53-66 ◽  
Author(s):  
A Bartolazzi ◽  
R Peach ◽  
A Aruffo ◽  
I Stamenkovic
Keyword(s):  
Tumor Growth ◽  
Cell Attachment ◽  
Tumor Development ◽  
Tumor Formation ◽  
Wild Type ◽  
Cd44 Isoforms ◽  
Secondary Tumor ◽  
Mediate Cell ◽  
Melanoma Growth

CD44 is implicated in the regulation of tumor growth and metastasis but the mechanism by which expression of different CD44 isoforms determines the rate of primary and secondary tumor growth remains unclear. In the present study we use a human melanoma transfected with wild-type and mutant forms of CD44 to determine which functional property of the CD44 molecule is critical in influencing tumor behavior. We show that expression of a wild-type CD44 isoform that binds hyaluronic acid augments the rapidity of tumor formation by melanoma cells in vivo, whereas expression of a CD44 mutant, which does not mediate cell attachment to hyaluronate, fails to do so. The importance of CD44-hyaluronate interaction in tumor development is underscored by the differential inhibitory effect of soluble wild-type and mutant CD44-Ig fusion proteins on melanoma growth in vivo. Whereas local administration of a mutant, nonhyaluronate binding, CD44-Ig fusion protein has no effect on subcutaneous melanoma growth in mice, infusion of wild-type CD44-Ig is shown to block tumor development. Taken together, these observations suggest that the tumor growth promoting property of CD44 is largely dependent on its ability to mediate cell attachment to hyaluronate.

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