Reduced Level of CD44 and Hyaluronan Associated with Unfavorable Prognosis in Clinical Stage I Cutaneous Melanoma

Karjalainen, Jari; Tammi, Raija; Tammi, Markku; Eskelinen, Matti; Ågren, Ulla M.; Parkkinen, Jyrki; Alhava, Esko; Kosma, Veli Matti

doi:10.1016/s0002-9440(10)64608-1

Cited by 92 publications

(66 citation statements)

References 49 publications

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“…Inconsistencies in this pattern, however, are also documented, suggesting that individual cancers utilize widely differing pathways during the process of malignant transformation and progression. [62][63][64][65] There was no toxicity observed with the hyaluronidase treatment. The specification insert for the testicular hyaluronidase preparation available for clinical use (Wydase) indicates that an LD 50 in cats and dogs could not be achieved.…”

Section: Discussionmentioning

confidence: 92%

Hyaluronidase reduces human breast cancer xenografts in SCID mice

Shuster

Frost

Csóka

et al. 2002

Intl Journal of Cancer

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A hyaluronan-rich environment often correlate with tumor progression. and may be one mechanism for the invasive behavior of malignancies. Eradication of hyaluronan by hyaluronidase administration could reduce tumor aggressiveness and would provide, therefore, a new anti-cancer strategy. Hyaluronan interaction with its CD44 receptor and the resulting signal transduction events may be among the mechanisms for hyaluronan-associated cancer progression. We have shown previously that hyaluronidase treatment of breast cancer cells in vitro not only eradicates hyaluronan but also modifies expression of CD44 variant exons of tumor cells. We now determine if such effects occur in vivo and if it is accompanied by tumor regression. SCID mice bearing xenografts of human breast carcinomas were given intravenous hyaluronidase. Tumor volumes decreased 50% in 4 days. Tumor sections showed decreased hyaluronan. Intensity of staining for CD44s was not affected, whereas staining for specific CD44 variant exon isoforms was greatly reduced in residual tumors. Necrosis was not evident. Hyaluronidase, used previously as an adjunct in cancer treatment, presumably to enhance penetration of chemotherapeutic drugs, may itself have intrinsic anti-cancer activity. Removing peritumor hyaluronan appears to cause an irreversible change in tumor metabolism. Continuous hyaluronan binding to CD44 variant exon isoforms may also be required to stabilize inherently unstable isoforms that participate perhaps in tumor progression. Further investigation is required to confirm a cause and effect relationship between loss of hyaluronan, changes in CD44 variant exon expression and tumor reduction. If confirmed, hyaluronidase may provide a new class of anti-cancer therapeutics and one without toxic side effects.

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Section: Discussionmentioning

confidence: 92%

Hyaluronidase reduces human breast cancer xenografts in SCID mice

Shuster

Frost

Csóka

et al. 2002

Intl Journal of Cancer

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“…CD44 is a structurally variable and multifunctional cell surface glycoprotein expressed on most cell types (Karjalainen et al, 2000). To date, it is the best characterized transmembrane hyaluronan receptor and because of its wide distribution is considered to be the major hyaluronan receptor on most cell types (Tzircotis et al, 2005).…”

Section: Interactions With Hyaladherinsmentioning

confidence: 99%

Hyaluronic acid (hyaluronan): a review

Nečas¹,

Bartošíková²,

Brauner³

et al. 2008

Vet. Med.

840

646

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Hyaluronic acid (HA) is a high molecular weight biopolysacharide, discovered in 1934, by Karl Meyer and his assistant, John Palmer in the vitreous of bovine eyes. Hyaluronic acid is a naturally occurring biopolymer, which has important biological functions in bacteria and higher animals including humans. It is found in most connective tissues and is particularly concentrated in synovial fluid, the vitreous fluid of the eye, umbilical cords and chicken combs. It is naturally synthesized by a class of integral membrane proteins called hyaluronan synthases, and degraded by a family of enzymes called hyaluronidases. This review describes metabolisms, different physiological and pathological functions, basic pharmacological properties, and the clinical use of hyaluronic acid. Keywords: hyaluronic acid; metabolism; toxicityList of abbreviations CD44 = cell surface glycoprotein; CDC37 = intracellular HA-binding protein; Da = dalton; DNA = deoxynucleotid acid; ECM = extracellular matrix; EM = electron microscopy; GHAP = glial hyaluronate-binding protein; GIT = gastrointestinal tract; HA = hyaluronic acid; HARE = hyaluronic acid receptor for endocytosis; HAS1, HAS2, and HAS3 = types of hyaluronan synthases 1, 2 and 3; IHABP = intracellular HA-binding protein; IMP = integral membrane protein; IL-1 = interleukine 1; LM = light microscopy; LYVE-1 = lymphatic vessel endocytic receptor; MRHD = maximum recommended human dose; NS = normal saline; OA = osteoarthrosis; P-32 = protein-32; RHAMM = receptor for hyaluronic acid mediated mobility; RHAMM/IHABP = receptor for hyaluronic acid mediated mobility/intracellular HA-binding protein; TDLo = toxic dose low; TIMP-1 = tissue inhibitor of matrix metalloproteiness 1;TNF-α = tumor necrosis factor alpha; TSG-6 = tumor necrosis factor-α-stimulated gene-6; t 1/2 = half-life; UDP = uridine diphosphate

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“…12 Specifically, it has been shown that loss of CD44 in some kinds of tumor, like cervical carcinomas, neuroblastomas, prostate carcinomas, melanomas, and small cell lung carcinomas, correlates with increased aggressiveness of these tumors. [13][14][15][16][17] It has been hypothesized that the loss of CD44 may facilitate the abrogation of epithelialmesenchymal interactions in some tumors, leading to a more metastatic phenotype. 12 Recently, a positive regulator of CD44, BRG-1, has been identified as a critical regulator of CD44 expression.…”

mentioning

confidence: 99%

Downregulation of BRG-1 repressed expression of CD44s in cervical neuroendocrine carcinoma and adenocarcinoma

et al. 2006

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Neuroendocrine carcinomas of the uterine cervix are rare tumors with early metastases, highly aggressive clinical behavior, and poor clinical outcome. Several adhesion molecules like cadherins have been tested in an attempt to explain their unique characteristics. Cluster differentiation 44 (CD44) is a widely expressed cell surface glycoprotein that serves as an adhesion molecule in cell-to-substrate and cell-to-cell interaction. We have examined the expression of the standard CD44 (CD44s) by immunohistochemical stains in the paraffinembedded cervical neoplasm tissue of 17 cases of primary cervical neuroendocrine carcinoma, 28 cases of cervical adenocarcinoma, and 50 cases of cervical squamous cell carcinoma. Loss of CD44s expression was found in 16 of 17 neuroendocrine carcinomas, 14 of 28 adenocarcinomas, and three of 50 squamous cell carcinomas. The differences were statistically significant. We also examined immunohistochemically the expression of the BRG-1 subunit of the SWI-SNF complex, which has been reported to regulate the expression of CD44 in all cases. Loss of BRG-1 expression was observed in 12/16, 6/14, and 1/3 CD44s-negative neuroendocrine carcinomas, adenocarcinomas, and squamous cell carcinomas, respectively. This study suggests that loss of the CD44s molecule may imply special biological behaviors of cervical neuroendocrine carcinomas, and loss of expression of BRG-1 may contribute to this.

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Reduced Level of CD44 and Hyaluronan Associated with Unfavorable Prognosis in Clinical Stage I Cutaneous Melanoma

Cited by 92 publications

References 49 publications

Hyaluronidase reduces human breast cancer xenografts in SCID mice

Hyaluronidase reduces human breast cancer xenografts in SCID mice

Hyaluronic acid (hyaluronan): a review

Downregulation of BRG-1 repressed expression of CD44s in cervical neuroendocrine carcinoma and adenocarcinoma

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