Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid

Ahrens, Tom; Sleeman, Jonathan; Schempp, Christoph M.; Howells, Norma; Hofmann, Martin; Ponta, Helmut; Herrlich, Peter; Simon, Jan C.

doi:10.1038/sj.onc.1204435

Cited by 125 publications

(104 citation statements)

References 47 publications

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“…Breast cancer cells were heterogeneous with respect to expression of a variety of cell surface markers (including CD44, CD24, and B38.1). CD24 and CD44 are adhesion molecules whereas B38.1 has been described as a breast͞ ovarian cancer-specific marker (17)(18)(19). To determine whether these markers could distinguish tumorigenic from nontumorigenic cells, flow cytometry was used to isolate cells that were positive or negative for each marker from passage 1 T1 or T2 cells.…”

Section: Resultsmentioning

confidence: 99%

Prospective identification of tumorigenic breast cancer cells

Al-Hajj

Wicha

Benito-Hernández

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

9,279

187

8,222

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Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies

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Section: Resultsmentioning

confidence: 99%

Prospective identification of tumorigenic breast cancer cells

Al-Hajj

Wicha

Benito-Hernández

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

9,279

187

8,222

View full text Add to dashboard Cite

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“…These oligomers also inhibit hyaluronan production (Misra et al, 2006). Over-expression of soluble CD44 in mouse mammary carcinoma cells or in human melanoma cells has been shown to induce apoptosis or cell cycle arrest in vivo and thus inhibit growth, local invasion and metastasis (Ahrens et al, 2001;Peterson et al, 2000;Yu et al, 1997). No significant effects were obtained in these studies if the soluble CD44 was mutated such that hyaluronan binding was reduced.…”

Section: Hyaluronan Cd44 and Emmprinmentioning

confidence: 72%

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

Toole

Slomiany

2008

Drug Resistance Updates

160

140

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Hyaluronan is not only an important structural component of extracellular matrices but also interacts with cells during dynamic cell processes such as occur in cancer. Consequently, interactions of hyaluronan with tumor cells play important cooperative roles in various aspects of malignancy. Hyaluronan binds to several cell surface receptors, including CD44, thus leading to co-regulation of signaling pathways that are important in regulation of multidrug resistance to anticancer drugs, in particular anti-apoptotic pathways induced by activation of receptor tyrosine kinases. Emmprin, a cell surface glycoprotein of the Ig superfamily, stimulates hyaluronan production and downstream signaling consequences. Emmprin and CD44 also interact with various multidrug transporters of the ABC family and monocarboxylate transporters associated with resistance to cancer therapies. Moreover, hyaluronan-CD44 interactions are critical to these properties in the highly malignant, chemotherapy-resistant cancer stem-like cells. Perturbations of the hyaluronan-CD44 interaction at the plasma membrane by various antagonists result in attenuation of receptor tyrosine kinase and transporter activities and inhibition of tumor progression in vivo. These antagonists, especially small hyaluronan oligomers, may be useful in therapeutic strategies aimed at preventing tumor refractoriness or recurrence due to drug-resistant sub-populations within malignant cancers.

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“…83 Soluble CD44 and RHAMM mutated to eliminate HA binding ability did not exhibit any antitumor effects, suggesting that interference with HA binding between the cell and the tumor HA matrix may also contribute to decreased tumor growth. 84,85 The above studies showed that decreased tumor growth by over-expression of soluble HA binding proteins is due to both increased apoptosis and physical mechanisms of CD44-matrix disruption. 83 -85, 87, 88 These results suggest that either mechanism may be a potential avenue for improved anti-cancer therapeutics.…”

Section: Targeting To the Hyaluronan Matrixmentioning

confidence: 99%

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

2008

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The complex system involved in the synthesis, degradation, and binding of the high molecular weight glycosaminoglycan hyaluronic acid (hyaluronan or HA) provides a variety of structures that can be exploited for targeted cancer therapy. In many cancers of epithelial origin there is an up-regulation of CD44, a receptor that binds HA. In other cancers, HA in the tumor matrix is over-expressed. Both CD44 on cancer cells and HA in the matrix have been targets for anti-cancer therapy. Even though CD44 is expressed in normal epithelial cells and HA is part of the matrix of normal tissues, selective targeting to cancer is possible. This is because macromolecular carriers predominantly extravasate into the tumor and not normal tissue; thus CD44-HA targeted carriers administered intravenously localize preferentially into tumors. Anti-CD44 antibodies have been used in patients to deliver radioisotopes or mertansine for treatment of CD44 expressing tumors. In early phase clinical trials, patients with breast or head and neck tumors treated with anti-CD44 conjugates experienced stabilized disease. A dose-limiting toxicity was associated with distribution of the antibody-drug conjugate to the skin, a site in the body with a high level of CD44. HA has been used as a drug carrier and a ligand on liposomes or nanoparticles to target drugs to CD44 over-expressing cells. Drugs can be attached to HA via the carboxylate on the glucuronic acid residue, the hydroxyl on the Nacetylglucosamine, or the reducing end which are located on a repeating disaccharide. Drugs delivered in HA-modified liposomes exhibited excellent anti-tumor activity both in vitro and in murine tumor models. The HA matrix is also a potential target for anti-cancer therapies. By manipulating the interaction of HA with cell surface receptors, either by degrading it with hyaluronidase or by interfering with CD44-HA interactions using soluble CD44 proteins, tumor progression was blocked. Finally, cytotoxic drugs or pro-drug converting enzymes can be attached to the HA matrix to generate a cytotoxic fence around the tumor. This review describes how the complex interplay among cancer biology, the CD44-HA interaction, drug carriers and drug targeting has been used to improve anti-cancer therapies. As these approaches evolve, they hold forth the prospect of significantly improved targeted anti-cancer treatments. KeywordsAntibody; Biodistribution; Cancer; Chemotherapy; Drug-conjugate; EPR effect; Liposome; Polymer; Prodrug; Recombinant Protein The Biology of the CD44-Hyaluronan InteractionHyaluronan (HA) (Figure 1) is a high molecular weight glycosaminoglycan, extracellular matrix component essential for proper cell growth, organ structural stability, and tissue organization. The amount of HA in a tissue depends upon on a complex interplay among HA synthesis by HA synthases, 1 HA internalization by cell surface receptors, 2 Interference with the CD44-HA interaction by either targeting drugs to CD44, 14 targeting drugs to the HA matrix 15 or interfering with HA ma...

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Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid

Cited by 125 publications

References 47 publications

Prospective identification of tumorigenic breast cancer cells

Prospective identification of tumorigenic breast cancer cells

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

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