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Classification and Evaluation of Cancer Markers

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Tumors are high-risk and high-mortality diseases that pose a serious threat to human health. A large number of studies and prevention data confirm that early diagnosis and early treatment are the most effective ways to prevent and treat cancer and reduce mortality. Therefore, the search for cancer markers that can be used for early diagnosis has become the focus of attention.

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However, in addition to poor differentiation, easy metastasis and high-speed proliferation, malignant tumor cells are completely equivalent to normal cells in cytological behavior. No specific expression products or shedding components have been found so far, or various malignant cancer markers have not yet been discovered. This brings problems to tumor diagnosis and immunotherapy.The ideal specific cancer markers must meet the following requirements: (1) unique to a certain tumor; (2) related to tumor size and stage; (3) therapeutic monitoring; (4) prognosis; (5) Does not intersect with healthy people and other diseases. Cancer markers that meet these criteria have not been discovered so far and may never be found. In recent years, all cancer markers used in clinical practice are mostly tumor-associated antigens, or some normal people also have trace amounts, but the amount is different. In any case, finding tumor-specific antigens is still a hot spot for cancer research because of the refractory tumors and the need for biotherapy.

Classification of common cancer markers:

1. Cancer Antigen 19-9 (CA19-9)

The carbohydrate antigen CA19-9 is a monoclonal antibody numbered 1116NS19-9 obtained by Koprowski et al. in 1979 using a human colon cancer cell line to immunize BALB/c pure mice and hybridize with myeloma. A class of tumor-associated carbohydrate antigens, the antigen recognized by the monoclonal antibody is named the carbohydrate antigen CA19-9. CA19-9 is a tumor-associated antigen, which is related to Lewis blood group components and can be present on normal tissue cells. It is not unique to tumor cells. It is mainly found in epithelial cells such as the stomach, intestine and pancreas of the fetus. The biliary cells and the stomach, colon, endometrium and salivary gland epithelium can also be synthesized. In certain malignant tumors, CA19-9 in body fluids is often at a high level. Observing the changes of CA19-9 in vivo is conducive to early detection of the above-mentioned malignant tumors of organs, and has certain differential significance for the benign and malignant tumors.

CA19-9 is detectable in serum, tumors, non-neoplastic diseases, and normal humans, but there are significant differences in CA19-9 levels in benign and malignant diseases. In benign diseases, normal people, serum CA19-9 elevation is usually low or transient, mostly below 100U/ml.In malignant tumors, the detection rate of different organs is different. At present, the increase of serum CA19-9 is more common in digestive tract tumors, especially pancreatic tumors, followed by biliary tract, colon, liver and stomach. In lung cancer, breast cancer and ovarian cancer. There is also a certain detection rate. The concentration of CA19-9 and the positive detection rate in the same organ tumor are related to the pathological type. For example, the CA19-9 concentration of colorectal cancer is higher in adenocarcinoma, mucinous carcinoma and signet ring cell carcinoma, but in papillary gland. Cancer and phosphorus cancer are lower. There are many clinical reports on the sensitivity and specificity of serum CA19-9 in various tumors, which are different from the disease and the number of cases in the selected cases, but the general trend is consistent. In the pancreatic cancer, the detection rate of serum CA19-9 is the highest. The sensitivity of each family is about 79%, even as high as 90.2%, and the specificity is between 70% and 90%. It has been used as a test for pancreatic cancer. Preferred serological indicators. The sensitivity in cholangiocarcinoma, gastric cancer, colon cancer, and liver cancer was 67% to 86%, 31.5% to 68%, 50%, and 49% to 60.9%, respectively. The sensitivity in lung cancer and breast cancer is low, about 10%. Many studies have shown that the concentration of CA19-9 is related to tumor size, especially in pancreatic cancer and colon cancer. A large number of studies have shown that preoperative detection of CA19-9 levels can help to determine the prognosis of patients with cancer, especially for patients with pancreatic cancer, colon cancer, hepatobiliary tumors, and gastric cancer. Preoperative high CA19-9 is a prognostic factor. The chances of recurrence and metastasis are high and the survival time is often short.

The tumor marker CA19-9 is a tumor-associated antigen. This index has important significance in the diagnosis, curative effect, prognosis and postoperative monitoring of malignant tumors such as pancreatic cancer, cholangiocarcinoma, liver cancer, gastric cancer and colon cancer. However, its specificity is still low, and the detection rate varies from place to place. How to improve the clinical value of this marker remains to be further studied. The detection rate of CA19-9 varies from one report to another, and it is related to the selected method and the sensitivity of the selected kit, in addition to the difference in the condition and number of cases in the selected case. With the deepening of research, the emergence of more sensitive, more reliable, more reproducible, more convenient, more environmentally friendly and economical assays, the development of highly specific CA19-9 antibody will increase the value in tumor diagnosis.

2.Cancer Antigen 125 (CA 125)

CA125 is a heterogeneous high molecular weight mucin-like glycoprotein containing mainly galactose, N-acetylglucosamine and N-acetylaminogalactose chains. The protein is partially rich in serine and can be recognized as an antigen by the monoclonal antibody OC125, hence the name CA125. Although the CA125 antigen is a glycoprotein, it has both membrane-bound and episomal states. CA125 in plasma and body fluids binds to glycoproteins of different relative molecular masses, respectively, and has the smallest subunit of CA125 immunoreactivity.

CA125 is present in the body cavity epithelial cells of embryonic development and disappears several hours after birth, but reappears in ovarian cancer cells. Immunohistochemistry revealed that CA125 was found in fetal digestive tract epithelial cells, amnion, adult pleura, peritoneal mesothelial cells, fallopian tube endothelium, uterus and cervix, but no CA125 was found in adult and fetal ovarian epithelial cells. Under normal circumstances, CA125 does not enter the blood circulation, so the quality of CA125 is very low in healthy people and most benign diseases. CA125 can enter the blood circulation and various body fluids and exhibit high expression during the growth and metastasis of malignant tumors and when some non-tumor diseases progress. Elevated serum CA125 marker is a direct contact between the shed tumor cells and the systemic circulation when the "natural barrier" in the human body is destroyed, resulting in elevated serum CA125 levels. If the tumor is confined, CA125 has not yet reached the systemic circulation, and the level of CA125 in the blood is not high.

Serum CA125 has been widely used in ovarian cancer screening, diagnosis, disease monitoring, prognosis and treatment. Serum CA125 combined with a variety of tumor markers can greatly improve the diagnosis and differential diagnosis of ovarian cancer. The half-life of CA125 used during chemotherapy can better predict the patient's response to treatment and monitor disease. The quality of serum CA125 can predict the trend of the subject to develop ovarian cancer. Serum CA125 detection combined with CT for the follow-up examination of patients with ovarian epithelial cancer is more valuable for detecting tumor recurrence. In addition, the current experimental and clinical studies on the treatment of ovarian cancer with CA125 monoclonal antibody have made great progress, and may bring new hope for the treatment of ovarian cancer. Examining the test results of elevated serum CA125 to patients can greatly improve the rate of return visits and improve the enthusiasm of women for regular gynaecological examinations.

3. Cancer Antigen 27.29

Breast carcinoma-associated antigen CA27.29 is a glycoprotein antigen produced by the MUC-1 gene. The product of the MUC-1 gene is MUC-1, which is a transmembrane glycoprotein expressed by glandular epithelia. The function of MUC-1 is associated with anti-pathogens and cell signaling. While overexpressed MUC-1, glycosylation changes, and abnormally intracellular localization have been related to cancers. Besides, MUC-1 was found in many types of malignant cells such as breast, ovarian, pancreatic, lung and prostate carcinomas. It can be shed into the circulation of the patients who have breast cancer. Hence CA27-29 is a part of MUC-1 and it can be detected by specific antibodies.

Alterations in glycosylation of MUC-1 have great influence on its physiological and pathophysiological activity by affecting the interaction between the MUC-1 and other target proteins. It has been reported that the abnormal glycosylation of MUC-1 induces novel protein-protein interaction and increases the expression of phospho-IκB kinase (IKK)-β and phospho-inhibitor of nuclear factor kappa-B (IκB)-α which are the membranes of NF-κB family. By stimulation with inflammatory factors such as TNF-α, the cancer form MUC-1 induces activation of NF-κB members and interact with phopsho-p65, then moves to the nucleus to regulate the production of pro-inflammatory factors such as IL-6 and TNF-α. Then, the inflammatory cells like myeloid cells and neutrophils are recruited to the tumor site by the inflammatory cytokines. Moreover, the inflammatory cells are capable of enhancing tumor growth and progression by producing pro-inflammatory and pro-tumorigenic cytokines.

For patients with breast cancer and ovarian cancer metastasis, especially those who have no clinical symptoms after treatment, when the serum CA27.29 is checked regularly, it is found that patients with CA27.29 measured value greater than 40 U/mL are less than the measured value. Patients with 40 U/m L or 40 U/m L have a much lower survival rate. Serum C A27.29 levels can also be used as a predictor of cancer recurrence in other adenocarcinomas, such as metastatic colorectal cancer and pancreatic cancer patients, and tumor metastasis can be found significantly earlier than other imaging techniques. This method is of little significance for the diagnosis and diagnosis of breast cancer patients during the construction period. In addition, in some diseases or physiological conditions, such as benign tumors, serum CA 27.29 values may also increase in the first 3 months of pregnancy, so attention should be paid to differential diagnosis.

4. Cyclin D3 (CCND 3)

Encoded by CCND3 gene, CCND3 protein belongs to the highly conserved cyclin family. All the cyclin members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins act as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns. Different expressions contribute to the temporal coordination of each mitotic event. CCND3 forms a complex with CDK4 or CDK6, and functions as a regulatory subunit of those two proteins. A number of reports have revealed that CCND3 are involved in the phosphorylation of tumor suppressor protein Rb. The CDK4 activity associated with CCND3 was reported to be necessary for cell cycle progression through G2 phase into mitosis after UV radiation. Several transcript variants of CCND3 have been found so far.

CDKs promote cell cycle transitions in mammalian cells by phosphorylating key substrates cyclins. Abnormal expression of cyclins was reported to be involved in many cancers progression. Highly expression of Cyclin D3 was reported in a number of tumor cells. Cyclin D3 gene is amplified in bladder carcinoma in situ. Genomic changes disrupting the expression of Cyclin D3 are involved in the aberrant growth of several human B-lymphoid malignancies. Targeting Cyclin D3 by miR-138 induces cell cycle arrest in hepatocellular carcinoma. Furthermore, Cyclin D3 is selectively required for proliferative expansion of germinal center B cells. For breast cancer, CCND3 is overexpressed in human breast cancer cell lines and primary invasive breast cancers. In addition, E1AF promotes breast cancer cell cycle progression via upregulation of CCND3 transcription. All the studies reveal that CCND3 is the marker of many tumor cells.

Research and development of highly specific CCND3 antibody widely used in disease screening and therapeutic monitoring, providing key products to the research market and providing the highest value for the diagnosis and prognosis of many tumor cells

Reference

[1] Ni X G, Bai X F, Mao Y L, et al. The clinical value of serum CEA, CA19-9, and CA242 in the diagnosis and prognosis of pancreatic cancer [J]. Eur J Surg Oncol, 2005, 31(2):164-169.

[2] Gorp T V, Cadron I, Despierre E, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm[J]. 2011.

[3] Cen P, Duvic M P, Kurzrock R. Increased cancer antigen 27.29 (CA27.29) level in patients with mycosis fungoides[J]. Journal of the American Academy of Dermatology, 2008, 58(3):382-386.

[4] Büschges R, Weber R G, Actor B, et al. Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas.[J]. Brain Pathology, 2010, 9(3):435-442.

[5] Zheng G, Patolsky F, Yi C, et al. Multiplexed electrical detection of cancer markers with nanowire sensor arrays[J]. Nature Biotechnology, 2005, 23(10):1294.


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