• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Sep 1996; 149(3): 873–882.
PMCID: PMC1865145

Progressive loss of CD44 gene expression in invasive bladder cancer.


This study investigated CD44 gene expression at both the RNA and protein level in well differentiated superficial and in deeply invasive bladder carcinomas. Proteins were studied by immunohistochemistry using antibodies against standard (CD44s) and variant (CD44v) isoforms. mRNA was analyzed by reverse transcriptase polymerase chain reaction/Southern blotting and in situ hybridization. Immunostaining with antibodies against CD44s and CD44v2, -5 and -6 (exons 7, 10, and 11, respectively) showed that carcinoma cells in all papillary tumors expressed strong signals throughout the epithelium but especially in the basal layer, which abuts on the stroma. However, invasive tumors, which are believed to originate mainly from flat urothelial tumors or, less frequently, from papillary carcinomas, progressively lost CD44 proteins as they penetrated deeper and became less differentiated. This change was paralleled at the mRNA level, by the gradual loss of expression of CD44s and CD44v transcripts in deeply invasive tumors until they were virtually undetectable. Conversely, papillary tumors contained multiple higher molecular weight transcripts, suggesting that the loss of CD44 proteins in the more aggressive tumors is due to a disturbance in transcription. This concept was confirmed by in situ hybridization studies with a probe showing that substantial variant CD44 mRNA is located in the urothelium in papillary carcinomas but is absent from deeply invasive carcinomas. These results indicate that initially there is a striking increase in CD44 gene expression in early bladder carcinomas, relative to normal urothelium, but that this diminishes as the tumors acquire a more aggressive phenotype.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Matsumura Y, Tarin D. Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet. 1992 Oct 31;340(8827):1053–1058. [PubMed]
  • Tarin D, Bolodeoku J, Hatfill SJ, Sugino T, Woodman AC, Yoshida K. The clinical significance of malfunction of the CD44 locus in malignancy. J Neurooncol. 1995 Dec;26(3):209–219. [PubMed]
  • Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991 Apr 5;65(1):13–24. [PubMed]
  • Birch M, Mitchell S, Hart IR. Isolation and characterization of human melanoma cell variants expressing high and low levels of CD44. Cancer Res. 1991 Dec 15;51(24):6660–6667. [PubMed]
  • Sy MS, Guo YJ, Stamenkovic I. Distinct effects of two CD44 isoforms on tumor growth in vivo. J Exp Med. 1991 Oct 1;174(4):859–866. [PMC free article] [PubMed]
  • Merzak A, Koocheckpour S, Pilkington GJ. CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res. 1994 Aug 1;54(15):3988–3992. [PubMed]
  • Wielenga VJ, Heider KH, Offerhaus GJ, Adolf GR, van den Berg FM, Ponta H, Herrlich P, Pals ST. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res. 1993 Oct 15;53(20):4754–4756. [PubMed]
  • Mulder JW, Kruyt PM, Sewnath M, Oosting J, Seldenrijk CA, Weidema WF, Offerhaus GJ, Pals ST. Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. Lancet. 1994 Nov 26;344(8935):1470–1472. [PubMed]
  • Joensuu H, Klemi PJ, Toikkanen S, Jalkanen S. Glycoprotein CD44 expression and its association with survival in breast cancer. Am J Pathol. 1993 Sep;143(3):867–874. [PMC free article] [PubMed]
  • Kaufmann M, Heider KH, Sinn HP, von Minckwitz G, Ponta H, Herrlich P. CD44 variant exon epitopes in primary breast cancer and length of survival. Lancet. 1995 Mar 11;345(8950):615–619. [PubMed]
  • Terpe HJ, Koopmann R, Imhof BA, Günthert U. Expression of integrins and CD44 isoforms in non-Hodgkin's lymphomas: CD44 variant isoforms are preferentially expressed in high-grade malignant lymphomas. J Pathol. 1994 Oct;174(2):89–100. [PubMed]
  • Washington K, Gottfried MR, Telen MJ. Expression of the cell adhesion molecule CD44 in gastric adenocarcinomas. Hum Pathol. 1994 Oct;25(10):1043–1049. [PubMed]
  • Kainz C, Kohlberger P, Sliutz G, Tempfer C, Heinzl H, Reinthaller A, Breitenecker G, Koelbl H. Splice variants of CD44 in human cervical cancer stage IB to IIB. Gynecol Oncol. 1995 Jun;57(3):383–387. [PubMed]
  • Hong RL, Pu YS, Hsieh TS, Chu JS, Lee WJ. Expressions of E-cadherin and exon v6-containing isoforms of CD44 and their prognostic values in human transitional cell carcinoma. J Urol. 1995 Jun;153(6):2025–2028. [PubMed]
  • Gross N, Beretta C, Peruisseau G, Jackson D, Simmons D, Beck D. CD44H expression by human neuroblastoma cells: relation to MYCN amplification and lineage differentiation. Cancer Res. 1994 Aug 1;54(15):4238–4242. [PubMed]
  • Fujita N, Yaegashi N, Ide Y, Sato S, Nakamura M, Ishiwata I, Yajima A. Expression of CD44 in normal human versus tumor endometrial tissues: possible implication of reduced expression of CD44 in lymph-vascular space involvement of cancer cells. Cancer Res. 1994 Jul 15;54(14):3922–3928. [PubMed]
  • Salmi M, Grön-Virta K, Sointu P, Grenman R, Kalimo H, Jalkanen S. Regulated expression of exon v6 containing isoforms of CD44 in man: downregulation during malignant transformation of tumors of squamocellular origin. J Cell Biol. 1993 Jul;122(2):431–442. [PMC free article] [PubMed]
  • Bostwick DG. Natural history of early bladder cancer. J Cell Biochem Suppl. 1992;16I:31–38. [PubMed]
  • Melamed MR. Papillary tumors of the bladder. J Cell Biochem Suppl. 1992;16I:44–47. [PubMed]
  • Matsumura Y, Hanbury D, Smith J, Tarin D. Non-invasive detection of malignancy by identification of unusual CD44 gene activity in exfoliated cancer cells. BMJ. 1994 Mar 5;308(6929):619–624. [PMC free article] [PubMed]
  • Czerniak B, Cohen GL, Etkind P, Deitch D, Simmons H, Herz F, Koss LG. Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas. Hum Pathol. 1992 Nov;23(11):1199–1204. [PubMed]
  • Matsumura Y, Sugiyama M, Matsumura S, Hayle AJ, Robinson P, Smith JC, Tarin D. Unusual retention of introns in CD44 gene transcripts in bladder cancer provides new diagnostic and clinical oncological opportunities. J Pathol. 1995 Sep;177(1):11–20. [PubMed]
  • Yoshida K, Bolodeoku J, Sugino T, Goodison S, Matsumura Y, Warren BF, Toge T, Tahara E, Tarin D. Abnormal retention of intron 9 in CD44 gene transcripts in human gastrointestinal tumors. Cancer Res. 1995 Oct 1;55(19):4273–4277. [PubMed]
  • Friedrichs K, Franke F, Lisboa BW, Kügler G, Gille I, Terpe HJ, Hölzel F, Maass H, Günthert U. CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. Cancer Res. 1995 Nov 15;55(22):5424–5433. [PubMed]
  • Liebert M, Washington R, Wedemeyer G, Carey TE, Grossman HB. Loss of co-localization of alpha 6 beta 4 integrin and collagen VII in bladder cancer. Am J Pathol. 1994 Apr;144(4):787–795. [PMC free article] [PubMed]
  • Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. [PubMed]
  • Neame SJ, Isacke CM. The cytoplasmic tail of CD44 is required for basolateral localization in epithelial MDCK cells but does not mediate association with the detergent-insoluble cytoskeleton of fibroblasts. J Cell Biol. 1993 Jun;121(6):1299–1310. [PMC free article] [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...