Significance of CD44 gene products for cancer diagnosis and disease evaluation

doi:10.1016/0140-6736(92)93077-Z

The Lancet

Volume 340, Issue 8827, 31 October 1992, Pages 1053-1058

https://doi.org/10.1016/0140-6736(92)93077-Z Get rights and content

Abstract

With increasing emphasis on the early detection of cancer, the search is on for reliable markers that will be clinically helpful in the diagnosis of small tumours and in the assessment of their metastatic potential. This report presents evidence that an abnormal pattern of activity of the CD44 gene is a promising candidate for both of these purposes in various types of malignancy. By a mechanism known as alternative splicing this gene can produce different messenger RNA molecules (transcripts) which are detectable, after amplification, as separate bands in electrophoretic gels. In neoplasia many abnormal variant transcripts are produced. A previous finding in animal experiments, that one such variant might be important in metastasis, prompted our study of human tumour tissue, benign and malignant, and of corresponding normal tissues. We studied tumour tissue from 34 patients with neoplastic disease (mostly breast or colon cancer) and normal or non-malignant diseased breast or colonic tissue from 11 patients and peripheral blood leucocytes from 4 healthy volunteers. CD44 gene activity was studied by amplifying messenger RNA with the polymerase chain reaction (PCR) followed by electrophoresis and blot hybridisation. In malignant tissues there was gross overproduction of each of 9 or more alternatively-spliced large molecular variants in all samples, whereas in the control samples only the standard product was routinely detected with occasional minimal quantities of one or two small variants. Furthermore, the band pattern permitted differentiation between the 23 cases with metastatic tumours of the breast or colon and the 8 with no detectable metastases. Calibration studies seeding blood with tumour cells showed that the technique can detect as few as 10 tumour cells among 10⁷ leucocytes (1 ml of blood). Analysis of CD44 splice variants may prove to have applications not just to the early detection of metastatic potential in surgical biopsy specimens but also, if our findings are confirmed, in readily available bodily fluids, to the early diagnosis of cancer in screening programmes, to the assessment of remaining disease in the body and to the early detection of recurrences.

References (12)

P. Frost et al.
Clinical imlications of metastatic process
Lancet
(1992)
Dg Jackson et al.
Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain
J Biol Chem
(1992)
I. Stamenkovic et al.
A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family
Cell
(1989)
U. Gunthert et al.
A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells
Cell
(1991)
Cwj Smith et al.
Alternative splicing in the control of gene expression
Annu Rev Genet
(1989)

There are more references available in the full text version of this article.

Cited by (465)

CNTs mediated CD44 targeting; a paradigm shift in drug delivery for breast cancer
2020, Genes and Diseases
Citation Excerpt :
However, the expression pattern and extent both play a vital role in drug resistance. In a study, it was reported that cells are having overexpression of CD44v6 treated with standard chemotherapeutic drugs shown significant higher viability and clonogenicity in colon cancer over cells which lacks expression of CD44v6 variants.53 CD44 represents a class of cell surface adhesion glycoprotein plays a vital role in cell–cell interaction.
The breast cancer is one of the most common cancer affecting millions of lives worldwide. Though the prevalence of breast cancer is worldwide; however, the developing nations are having a comparatively higher percentage of breast cancer cases and associated complications. The molecular etiology behind breast cancer is complex and involves several regulatory molecules and their downstream signaling. Studies have demonstrated that the CD44 remains one of the major molecule associated not only in breast cancer but also several other kinds of tumors. The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well. The Carbon nanotubes (CNTs) have shown tremendous scope in delivering the drug by targeting a particular receptor and molecules. Functionalized CNTs including both SWCNTs and MWCNTs are a pioneer in drug delivery with higher efficacy. The present work emphasized mainly on the potential of CNTs including both SWCNTs and MWCNTs in drug delivery for anti-cancerous therapy. The review provides a comprehensive overview of the development of various CNTs and their validation for effective drug delivery. The work focus on drug delivery approaches for breast cancer, precisely targeting CD44 molecule.
Synergistic Enhancement of Cellular Uptake With CD44-Expressing Malignant Pleural Mesothelioma by Combining Cationic Liposome and Hyaluronic Acid–Lipid Conjugate
2019, Journal of Pharmaceutical Sciences
Malignant pleural mesothelioma (MPM) is a highly aggressive form of cancer, with a median survival of less than 1 year. It is well known that the hyaluronan (HA) receptor CD44 is highly expressed by MPM cells and is reported to be correlated with a poor prognosis. We herein report on the development of a new type if drug delivery system against CD44 that involves the use of lipid nanoparticles (LNPs) equipped with a new type of HA derivative. In this study, we evaluated HA-lipid conjugation (HAL) via the end of the HA molecule through reductive amination, a process that allowed the carboxylate group to remain intact. As a result, the HAL-modified LNP appears to be a potent nanoparticle for dealing with MPM. Surprisingly, the use of a combination of a cationic lipid and HAL had a synergistic effect on cellular uptake in MPM and consequently permitted an anti-cancer drug such as cis-diamminedichloro-platinum(II) (CDDP). Intrapleural injection of CDDP-loaded HAL-LNP (1.5 mg/kg as CDDP) per week significantly suppressed the progression of this type of cancer in an MPM orthotopic model. These results suggest that HAL-modified LNP represents a potent delivery system for MPM cells that express high levels of CD44.
Multifunctional nanotheranostic gold nanocages for photoacoustic imaging guided radio/photodynamic/photothermal synergistic therapy
2019, Acta Biomaterialia
Citation Excerpt :
Therefore, we chose 24 h post-injection of AuNCs-HA to study the in vivo tumor imaging and therapy. It is reported that HA shows targeting capability to CD44-overexpressing breast cancers [39,52]. Therefore, to demonstrate the targeting efficiency of AuNCs-HA, we evaluated the targeting ability of AuNCs-HA by examination of the concentration of Au in tumors treated with AuNCs, AuNCs-PEG or AuNCs-HA using ICP-OES (Fig. S9).
In this work, we developed a novel multifunctional nanoplatform based on hyaluronic acid modified Au nanocages (AuNCs-HA). The rational design of AuNCs-HA renders the nanoplatform three functionalities: (1) AuNCs-HA with excellent LSPR peak in the NIR region act as contrast agent for enhanced photoacoustic (PA) imaging and photothermal therapy (PTT); (2) the nanoplatform with high-energy rays (X-ray) absorption and auger electrons generation acts as a radiosensitizer for radiotherapy; (3) good photocatalytic property and large surface area make AuNCs-HA a photosensitive agent for photodynamic therapy (PDT). In vivo results demonstrated that AuNCs-HA presented excellent PA imaging performance after intravenous injection, which provided contour, size, and location information of the tumor. Moreover, because AuNCs-HA could combine radiotherapy and phototherapy together, the tumors treated with AuNCs-HA showed complete growth inhibition, comparing to that with each therapy alone. Taken together, our present study demonstrates that AuNCs-HA is of great potential as a multifunctional nanoplatform for PA imaging-guided radio- and photo-therapy of tumor.
In this study, a commendable theranostic nanoplatform based on hyaluronic acid modified AuNCs (AuNCs-HA) was developed. In our approach, the dilute solution of Gold(III) chloride is slowly dripped into Ag nanocubes solution, then the Au nanocages were obtained by redox reaction, and followed by HA modification. We explored them, simultaneously, as radiosensitizers for RT, photosensitizers for PDT, and therapeutic agents for PTT. Compared to that of each therapies alone, the combination of radio-therapy and photo-therapy results in a considerably improved tumor eliminating effect and efficiently inhibited tumor growth. In addition, AuNCs-HA exhibited remarkably strong PA signals for precise identification of the location, size, and boundary of the tumor, thereby facilitating imaging-guided therapy. In brief, our design of AuNCs-HA represents a general and versatile strategy for building up cancer-targeted nanotheranostics with desired synergistic imaging and therapy functionalities.
Stimuli-responsive nanoparticles based on co-assembly of naturally-occurring biomacromolecules for in vitro photodynamic therapy
2018, Colloids and Surfaces A: Physicochemical and Engineering Aspects
Citation Excerpt :
These materials show good biodegradability and high compatibility, as HA can be selectively degraded by hyaluronidases [28]. Especially self-assembled nanoparticles of HA can accumulate in tumors not only through the EPR effect but also through the specific interactions between HA and CD44, a receptor that is overexpressed on various tumor cells [29,30], providing the nanoparticles with favorable tumor-targeting properties. In addition, overexpressed levels of hyaluronidases are found in various tumors [31–34], suggesting, that the loaded drugs can be preferentially released from the nanoparticles inside tumors.
Nanomaterials constructed by self-assembly of biomolecules are of particular interest as drug delivery carriers in biomedicine. However, supramolecular construction of nanoparticles by self-assembly of highly hydrophilic biomolecules such as hyaluronic acid still remains a formidable challenge due to their water solubility. Herein, we propose a strategy to fabricate stable nanoparticles by self-assembly of hyaluronic acid without the need of modification by hydrophobic groups. This strategy involves the electrostatic assembly of hyaluronic acid and naturally produced ε-polylysine and the in situ crosslinking by disulfide bonds. The resulting nanoparticles have the advantages of resistance to dilution, tunable size and surface charge, and efficient encapsulation of Chlorin e6 (Ce6), a photosensitizer for photodynamic therapy (PDT). In addition, the release of Ce6 from the nanoparticles is synergistically responsive to variations of pH and GSH levels. In vitro experiments reveal that the Ce6-loaded nanoparticles exhibit enhanced cellular uptake, improved phototoxicity, and unaltered biocompatibility as compared to unencapsulated Ce6, demonstrating that the nanoparticles constructed by self-assembly of hyaluronic acid are efficient and biocompatible drug delivery carriers for PDT agents.
OutSplice: A Novel Tool for the Identification of Tumor-Specific Alternative Splicing Events
2023, BioMedInformatics
Targeting CD44 Variant 5 with an Antibody–Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma
2023, Cancer Research

View all citing articles on Scopus

View full text

ORIGINAL ARTICLESSignificance of CD44 gene products for cancer diagnosis and disease evaluation

Abstract

Lancet

J Biol Chem

Cell

Cell

Alternative splicing in the control of gene expression

Annu Rev Genet

ORIGINAL ARTICLES
Significance of CD44 gene products for cancer diagnosis and disease evaluation