Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development (original) (raw)
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Inhibition of tumor growth in vivo with a soluble CD44-immunoglobulin fusion protein
Journal of Experimental Medicine, 1992
CD44H is the principal cell surface receptor for hyaluronate, which is a major glycosaminoglycan of the extracellular matrix. Expression of CD44H is enhanced in a variety of malignant tumors and correlates with tumor aggressiveness, supporting the notion that interaction between CD44H and hyaluronate may play an important role in tumor growth and dissemination. In this report we show that in vivo tumor formation by human lymphoma Namalwa cells, stably transfected with CD44H, can be suppressed by a soluble human CD44H-immunoglobulin fusion protein. Disruption of the interaction between CD44H and its physiologic ligands may provide a novel strategy for controlling tumor growth in vivo.
The American Journal of Pathology, 2000
Hyaluronan accumulates in ascites during intraperitoneal proliferation of TA3/St murine mammary carcinoma cells and at sites of their invasion of the peritoneal wall. To determine whether hyaluronan is functionally involved in these events, ascites tumor formation was compared in mice injected intraperitoneally with stable transfectants of TA3/St cells that overexpress soluble CD44, a hyaluronan-binding protein, versus in mice injected with transfectants expressing mutated soluble CD44 that does not bind hyaluronan. The soluble CD44 transfectants temporarily grew at a reduced rate within the peritoneal cavity, then went into G 1 arrest and were subsequently cleared from the peritoneum. However, transfectants overexpressing mutant soluble CD44 that does not bind hyaluronan exhibited similar ascites accumulation, growth rates, and cell-cycle profiles in vivo to wild-type and vector-transfected TA3/St cells, all of which continued to grow until the tumors became fatal. The soluble CD44-transfected TA3/St cells also failed to attach to and form tumors in the peritoneal wall. When grown in vitro in soft agar, the soluble CD44 transfectants exhibited a dramatic reduction in colony formation compared to wild-type, vector-transfected, and mutant soluble CD44-transfected TA3/St cells. Thus, perturbation of hyaluronan interactions by soluble CD44 has a direct effect on the growth characteristics of these tumor cells, leading to inhibition of anchorage-independent growth in vitro and ascites growth in vivo.
CD44H regulates tumor cell migration on hyaluronate-coated substrate
Journal of Cell Biology, 1992
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 s...
Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody
Cancer research, 1994
CD44 is a M(r) 90,000 surface glycoprotein believed to be involved in cell adhesion and migration. We investigated the role of CD44 in tumor growth and metastasis using human melanoma cell lines SMMU-1 and SMMU-2. Both SMMU-1 and SMMU-2 form tumors in the s.c. tissues when injected s.c. in SCID mice but only SMMU-2 metastasizes. Approximately one-half of SCID mice receiving injections of SMMU-2 s.c. develop metastatic tumors. SMMU-2 but not SMMU-1 expresses high levels of the hematopoietic form of CD44 and binds fluorescence-conjugated hyaluronic acid in vitro. GKW.A2 is a monoclonal antibody specific for human CD44 that can completely inhibit the binding of hyaluronic acid to SMMU-2 tumor cells in vitro. Moreover, in vivo injection of GKW.A3 inhibited the growth and metastatic potential of SMMU-2 tumor cells. Administration of GKW.A3 i.v. 1 week after s.c. tumor injection did not inhibit local tumor development but inhibited the formation of metastatic tumors and prolonged animal s...
Distinct effects of two CD44 isoforms on tumor growth in vivo
Journal of Experimental Medicine, 1991
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 ...
Tumor Cells Enhance Their Own CD44 Cleavage and Motility by Generating Hyaluronan Fragments
Journal of Biological Chemistry, 2005
Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that interacts with cell-surface receptors, including CD44. Although HA usually exists as a high molecular mass polymer, HA of a much lower molecular mass that shows a variety of biological activities can be detected under certain pathological conditions, particularly in tumors. We previously reported that low molecular weight HAs (LMW-HAs) of a certain size range induce the proteolytic cleavage of CD44 from the surface of tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we show that MIA PaCa-2, a human pancreatic carcinoma cell line, secreted hyaluronidases abundantly and generated readily detectable levels of LMW-HAs ranging from ϳ10to 40-mers. This occurred in the absence of any exogenous stimulation. The tumor-derived HA oligosaccharides were able to enhance CD44 cleavage and tumor cell motility. Inhibition of the CD44-HA interaction resulted in the complete abrogation of these cellular events. These results are consistent with the concept that tumor cells generate HA oligosaccharides that bind to tumor cell CD44 through the expression of their own constitutive hyaluronidases. This enhances their own CD44 cleavage and cell motility, which would subsequently promote tumor progression. Such an autocrine/paracrine-like process may represent a novel activation mechanism that would facilitate and promote the malignant potential of tumor cells.
Hyaluronan-CD44 interactions as potential targets for cancer therapy
FEBS Journal, 2011
It is becoming increasingly clear that signals generated in tumor microenvironments are crucial to tumor cell behavior, such as, survival progression, and metastasis. The establishment of these malignant behaviors requires that tumor cells acquire novel adhesion and migration properties to detach from their original sites for localizing into distant organs. CD44, an adhesion/homing molecule is a major receptor for the glycosaminoglycan hyaluronan, which is one of the major components of the tumor extracellular matrix (ECM). CD44, a multi structural and multifunctional molecule, detects changes in ECM components, and thus is well positioned to provide appropriate responses to changes in the microenvironment, i.e. engagement in cell-cell and cell-ECM interactions, cell traffic, lymph node homing, and presentation of growth factors/cytokines/ chemokines to co-ordinate signaling events that enable the cell responses that change in the tissue environment. The potential involvement of CD44variants (CD44v), especially CD44v4-v7 and CD44v6-v9 in tumor progression was confirmed for many tumor types in numerous clinical studies. Down regulation of the standard CD44 isoform (CD44s) in colon cancer is postulated to result in increased tumorigenicity. CD44v-specific functions could be due to their higher binding affinity for hyaluronan than CD44s. Alternatively, CD44v-specific functions could be due to differences in associating molecules, which may bind selectively to the CD44v exon. This review summarizes how the interaction between hyaluronan and CD44v can serve as a potential target for cancer therapy, in particular how silencing the CD44v can target multiple metastatic tumors.
The Hyaluronan/CD44 Axis: A Double-Edged Sword in Cancer
International Journal of Molecular Sciences
Hyaluronic acid (HA) receptor CD44 is widely used for identifying cancer stem cells and its activation promotes stemness. Recent evidence shows that overexpression of CD44 is associated with poor prognosis in most human cancers and mediates therapy resistance. For these reasons, in recent years, CD44 has become a treatment target in precision oncology, often via HA-conjugated antineoplastic drugs. Importantly, HA molecules of different sizes have a dual effect and, therefore, may enhance or attenuate the CD44-mediated signaling pathways, as they compete with endogenous HA for binding to the receptors. The magnitude of these effects could be crucial for cancer progression, as well as for driving the inflammatory response in the tumor microenvironment. The increasingly common use of HA-conjugated drugs in oncology, as well as HA-based compounds as adjuvants in cancer treatment, adds further complexity to the understanding of the net effect of hyaluronan-CD44 activation in cancers. In ...
Hyaluronate-independent metastatic behavior of CD44 variant-expressing pancreatic carcinoma cells
Cancer research, 1996
Several studies have demonstrated a correlation between the expression of CD44 variant isoforms and the ability of tumor cells to metastasize. The CD44 proteins carry amino acid sequence motifs that confer the ability to bind to the extracellular matrix component hyaluronate (HA). In this study, we investigated whether a CD44 variant previously shown to stimulate metastasis in a rat pancreatic carcinoma model (BSp73AS) is capable of binding to HA, and whether such binding is critical for metastasis. We show that transfection of this CD44 variant into BSp73AS cells increases the HA-binding capacity of the cells in a dose-dependent manner. Transfection of the same CD44 variant isoform into BDX2 cells also conferred strong HA-binding properties on these cells, but was insufficient to cause them to metastasize. Transfection of a surface-bound hyaluronidase into metastasizing BSp73AS cells bearing variant CD44 efficiently ablated the ability of these cells to bind to HA. However, in meta...