|Year : 2016 | Volume
| Issue : 1 | Page : 29-32
CD24 as a Molecular Marker in Ovarian Cancer: A Literature Review
Lu Huang1, Weiguo Lv2, Xiaofeng Zhao1
1 Department of Gynecology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
2 Department of Gynecologic Oncology, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
|Date of Submission||26-Jul-2015|
|Date of Acceptance||17-Jan-2016|
|Date of Web Publication||26-Feb-2016|
Department of Gynecology, Zhejiang Provincial People's Hospital, No. 158 Shangtang Road, Hangzhou 310014, Zhejiang
Source of Support: None, Conflict of Interest: None
Ovarian cancer is the most lethal gynecologic cancer, with a mortality rate of > 60%. Cancer stem cell (CSC) hypothesis offers an attractive explanation of chemoresistance, metastasis, etc., associated with the disease. However, there are still controversy and limitation in defining the CSC markers. CD24 is a mucin-type glycosyl-phosphatidylinositol-linked glycoprotein, expressed on the surface of cells, which serves as a normal receptor for P-selectin and is found involved in molecular adhesion and metastatic tumor spread. Expression rate of CD24 has been associated with progression of various cancers and poor survival rates. In this review, the function of CD24 in ovarian cancer, especially in ovarian CSC system, was discussed in an effort to broaden the interpretation of potential mechanism.
Keywords: Cancer, cancer stem cell, CD24, ovarian cancer
|How to cite this article:|
Huang L, Lv W, Zhao X. CD24 as a Molecular Marker in Ovarian Cancer: A Literature Review
. Cancer Transl Med 2016;2:29-32
| Introduction|| |
CD24 is a membrane glycoprotein composed of 27 amino acids with extensive core N- or O-linked glycosylation and P-selectin binding sites and is bound to the membrane via a glycosylphosphatidylinositol anchor.  The gene located on chromosome 6q21, a polymorphicallele, codes for CD24 which has a heterogeneous molecular weight ranging from 30 to 70 kDa.  CD24 is expressed on pre-B lymphocytes, neutrophils, and certain epithelial cells but not on normal T-cells, monocytes, and cells outside the blood system. As the expression of CD24 is affected by pedigree restrictions and physical development, it was used as a biomarker for distinguishing B-cells from T-cells.  Subsequent studies demonstrated that CD24 is also expressed in several other cancers such as B-cell leukemia, nonsmall cell lung carcinoma, neuroblastoma, rhabdomyosarcoma, and renal cell carcinoma. Furthermore, CD24 has been proved to be associated with tumor metastasis and prognosis.  Here, we discuss recent advances in the role of CD24 as a molecular marker in ovarian cancer by reviewing recent literature.
| The Role of CD24 in Tumor Invasion, Metastasis, and Progression|| |
It is known that CD24 is one of the ligands for P-selectin which is mainly expressed in thrombin-activated platelets and endothelial cells. Under physiological conditions, P-selectin is stored in intracellular granules and can be rapidly transferred to the surface when exposed to inflammatory molecules such as histamine and thrombin. Experiments have proved that like other selectins, binding of P-selectin to the cell can help reduce the shear force generated in the process of leukocyte adhesion to endothelium, and both anti-P-selectin and anti-CD24 antibodies can block it.  However, in pathological condition, CD24 promotes the adhesion of cancer cells to activated platelets and endothelial cells.  It has also been reported that the P-selectin-dependent binding of cancer cells to platelets, which plays a critical role in tumor metastasis, was enhanced when cancer cells were transfected with CD24. 
In addition, Schabath et al.  demonstrated that CD24 could bind to CXCR4 and regulate the stromal cell-derived factor 1α (SDF-1α) receptor. Reduced expression of CD24 may be associated with increased intracellular cholesterol, lipid rafts of CXCR4, and increased invasive ability. It has also been shown that CD24-low group had greater rate of tumorigenicity in breast cancer NOD/SCID mice model, which indicated that CD24 is an important molecule in the regulation of CXCR4.  It was reported that the carcinoma-associated fibroblasts (CAFs) promote the growth of breast cancer stem cells (CSCs) (CD44+/CD24−) and secrete more SDF-1α under co-culture condition compared to normal fibroblasts. Therefore, it was speculated that proliferation and invasion of CD44+/CD24− breast cancer cells are associated with CXCR4 signaling pathways via CAFs and SDF-1α. 
Ju et al. showed that the overexpression of CD24 could inhibit anti-apoptotic nuclear factor-kappa B (NF-kB) signaling pathway in CD44-positive tumor cells, which then accelerated apoptosis along with DNA damage. It was demonstrated that CD24 overexpression could decrease the phosphorylation level of c-Raf/MEK/MAPK signaling pathway which then down-regulate NF-kB signaling pathway. Hence, it was believed that the CD24-low cells participate in the anti-apoptotic mechanism.
Thomas et al. showed that CD24 is a target gene for hypoxia-inducible factor 1α (HIF-1α) transcription in bladder cancer UMUC-3 cell line. Increased expression of HIF-1α and hypoxic environment could promote CD24 overexpression, and consistency of expression of HIF-1α and CD24 was confirmed by in vitro experiment, which revealed other possible mechanisms of promoting tumor progression.
Mierke et al. demonstrated that the mechanical force of contraction may vary with the change in CD24 expression and consequently alter cell adhesion. A125 lung cancer cell line was used in the study and showed that the rate of contraction was directly proportional to CD24 expression rate, similar to integrin1-β receptor molecule, and thus has a stronger adhesion and invasion.
Bretz et al.  used the cell lines A549, SKOV3ip, BxPC3, HS683, and SNB19 and showed that the overexpression of CD24 can increase the Src - Y416 phosphorylation level, recruit Src to lipid rafts, and increase the targeted gene expression of STAT3 transcription factor. Contradictorily, under in vivo experiments using mouse model, CD24 antibody reduced the level of Src phosphorylation and STAT3 downstream gene expression and thereby altered the cell proliferation and the transfer capability.
Bretz et al. thereafter demonstrated that CD24 can change the expression of c-Src in a positive way, and both CD24 and c-Src could reverse the regulation of tissue factor pathway inhibitor-2 (TFPI-2), thus indirectly changing the cell proliferation, adhesion, invasion, and tumor growth. Silencing c-Src or CD24 can increase the expression of TFPI-2, which indicated that CD24 decreased the expression of TFPI-2 by downstream c-Src, and then finally changing the microenvironment for tumor, probably to break through the surrounding matrix. Immunohistochemical analysis of 1174 primary breast cancer cases showed that CD24 expression was negatively correlated with TFPI-2 and the prognosis of CD24-low/TFPI-2 high group was better than CD24-high/TFPI-2 low group. 
Buck et al. studied 2514 breast cancer patients and 4858 normal control subjects. They selected rs52812045 and rs3838646 CD24 polymorphic sites for analysis and found that for cases with body mass index < 25 and underwent neoadjuvant chemotherapy, CD24 Ala/Val is progression associated factor, but changes in allele were not associated with occurrence of breast cancer. To date, the mechanism by which CD24 Ala/Val modifies chemotherapy response and prognosis of breast cancer patients is still unclear. The authors suggested two hypotheses: (1) CD24 Ala/Val may directly impact the tumor cell phenotype, making them more aggressive, enhancing proliferation, and rendering them more sensitive to chemotherapy; (2) CD24 polymorphisms are genetic modifiers in autoimmune diseases, and the CD24 genotype may modulate the host antitumor immune response and could thereby modulate chemotherapy response as well as prognosis.
Under in vitro condition, interference of CD24 short hairpin RNA with SKOV3 cells resulted in decreased proliferation and increased apoptosis, which indicates that CD24 may play a role in progression of ovarian cancer. More detailed experiments are needed to explain detailed mechanism. 
| Increased Expression of CD24 in Ovarian Cancer and its Relevancy to Disease Staging and Prognosis|| |
A summary of meta-analysis reveals that unlike their benign forms, 68% of carcinomas including breast cancer, female genital system neoplasm, gastrointestinal cancer, urinary tract cancer, and skin cancer show CD24 overexpression. Besides, this overexpression was found to be significantly correlated with lymph node metastasis (odds ratio [OR] = 2.41; confidence interval [CI], 1.013-5.720; P = 0.047), clinical stages of cancer (OR = 1.59; 95% CI, 1.244-2.032; P < 0.001), and patient survival rate (hazard ratio = 2.13; 95% CI, 1.656-2.730; P < 0.001).  Japanese scholars sequenced the whole genome of 22 cases of epithelial ovarian cancer specimens and found 273 up-regulated genes and 387 down-regulated genes, among which CD24 was listed in up-regulated genes, suggesting its possible involvement in the progression of ovarian cancer. 
Gao et al. assessed the changes of CD24 expression in 92 cases of ovarian tumors, 12 benign tumors, 19 borderline tumors, and 61 epithelial ovarian cancers. The results suggested that CD24 expression rate positively correlated with the degree of malignancy, clinical stage, omentum metastasis, and expression of EP-CAM (an invasion-related molecule) while negatively correlated with degree of differentiation. Chen et al. obtained similar results from the analysis of ovarian cancer specimens reporting that the rate of CD24 expression is independent of the histological type but positively correlated with the degree of tumor differentiation, clinical stage, and the proliferation index using Ki-67 molecule. Wang et al. analyzed 53 cases of ovarian cancer specimens and found that the cytoplasmic CD24-positive subjects significantly correlated with International Federation of Gynecology and Obstetrics stage (P < 0.05). They are more likely to relapse and have poor prognosis compared to membrane CD24-positive subjects (P < 0.05). This study revealed the correlation of CD24 overexpression with grading and prognosis of ovarian epithelial carcinoma.  Schreiber et al. investigated morphological appearance of CD24 and Nanog in benign ovarian tumors, serous borderline tumors, and serous ovarian carcinomas and concluded that CD24 and Nanog might exert intrinsically synergistic effect to promote the malignant disease.
| CD24 is One of the Cancer Stem Cell Markers|| |
The tumor metastasis is divided into two processes: (1) tumor microenvironment change and distant spread and (2) successful colonization of the tumor cells. The first process includes matrix hydrolysis by metalloproteinases, epithelial-mesenchymal transition, and cancer cell migration into the circulatory and lymphatic system. Not all migrated tumor cells can form colonies in the latter process. A few highly tumorigenic, colony forming cells are considered CSCs. The most important characteristic of these CSCs is the ability to initiate tumor, and they are characterized by aggressive migration/invasion, drug-resistance, and anti-apoptotic capacity.  It is considered that the residual CSC is the root of tumor recurrence.
Breast cancer is the most widely and in-depth studied solid tumor, in which cancer cells with molecular marker CD44+/CD24− are found to have the capacity to initiate tumor and are considered the CSCs of breast cancer.  In pancreatic cancer, CD44+/CD24+ epithelial-specific antigen+ cells are considered to be CSCs.  This shows that the molecular labels of CSCs vary according to their source tissues. Ovarian CSC markers have also been actively explored. Gao et al. have detected the expression of related stem cell genes and proteins (including Nestin, β-catenin, Bmi-1, Oct4, Oct3/4, Notch 1, Notch 4, CD133, CD44, CD117, and CD24) in 20 cases of serous and mucinous ovarian cancer specimens. The results revealed that compared to CD24− cells, CD24+ cells have stronger resistance to chemotherapy drugs with higher self-renewal ability. Tumorigenesis test indicated that a single subcutaneous injection of 5000 CD24+ cells into the right and left flanks of nude mice could induce tumor formation while the same number of CD24− cells failed to do so.  Meirelles et al. sorted CD44+CD24+EP-CAM+Ecadherin-cells, which constituted for ≈ 1% of the total cells, using HOSE-4, HOSE-6, OVCAR-5, MOVCAR-7, and MOVCAR-8 (a mouse ovarian cancer cell line), OVCAR-3, SKOV-3, and IGROV-1 ovarian carcinoma cell lines. Compared to other cells, these CD44+CD24+Ep-CAM+Ecadherin-cells, with a shorter cell cycle and progression-free survival, are more efficient to form tumor spheroids in the experiment of tumor spheroid formation. Besides, their growth and proliferation were mostly unaltered under the stimulation of doxorubicin or cisplatin. However, Mullerian inhibiting substance could effectively reduce the colony forming ability of these cells by inhibiting cyclin-dependent kinase inhibitors.  Shi et al. found that CD24− population of mucinous ovarian cancer 3AO cell line had the same features with CSCs as assessed through flow sorting, drug-resistance test, and tumorigenesis test. Thereafter, Meng et al. confirmed that a subpopulation of cells with CD44+ CD24− markers in SKOV3 and OV90 cell lines also expressed CSC characteristics. It was also found that the ratio of tumor cells with CD44+/CD24− markers in ascites of a subgroup of primary ovarian cancer patients was more than 25%, and these patients were more likely to experience relapse with shorter median progression-free survival.  Besides, others showed that CD24+ and CD133+ cells have higher tumor sphere-forming capacity, and inhibition of JAK2 signaling dramatically reduced their metastasizing ability.  The markers of ovarian CSCs also included CD133, ALDH1, CD44, and CD117,  which indicated that the marker molecules may exist simultaneously or crosswise. The marker molecules which are screened from different cell lines, primary samples, or ascites specimens have a great diversity. In addition, a side population of cells with increased expression of ABCG2/BCRP1 or MDR1/ABCB1, which belong to the family of ATP-binding cassette transporters, can pump out lipophilic substances, such as Hoechst 33342. , These few cells with such special capability can survive in an unfavorable microenvironment and possess high tumorigenic ability.
It has also been reported that CD24 is not only closely related to breast cancer and ovarian cancer but also associated with colorectal cancer, prostate cancer, and pancreatic CSCs. However, such claim of CD24 and CD44 as CSC markers is still under question.  This is mainly because of the ubiquitous expression of the CD24 in both normal and CSCs added with the complex physiological and pathological action of the molecule itself. Besides, CD24 expression demonstrates certain correlation with pathological grade and clinical stage of the disease but shows no correlation to survival rate. At present, the enriched screening for ovarian CSCs remains difficult and controversial. Hence, screening for multiple molecular markers while exploring the mechanism of tumor development can be regarded as an excellent strategy.
| Conclusion|| |
A growing number of studies have found that although the surface adhesion molecules functioned normally under physiological conditions, they participated in the development of cancer under pathological conditions. The time from discovery of CD24 in the immune system to its localization on the solid tumor is < 20 years, and its further growth from breast CSC to other solid tumors is < 10 years, which reveals the importance of this molecule. Despite this growth, the underlying mechanism of CD24's involvement in tumor progression is still unclear. Moreover, the claim of CD24 as CSC marker is still debatable. A few studies suspect CD24+ cells while a few other studies consider CD24− cells as CSCs in ovarian cancer. Further studies in this regard will contribute to the knowledge of ovarian cancer and will assist in developing more effective treatment against this devastating disease.
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Conflicts of interest
There are no conflicts of interest.
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