Tumor Biomarkers

Cancer remains as a major public health challenge despite the effortful progress in cancer detection and therapy. A significant fraction of the US population will develop cancer during their lifetime, with over half a million individuals dying yearly from the disease (American Cancer Society, 2018). The goal to obtain control and knowledge over the disease is gaining speed and focus.

While cancer incidence across our ageing population is increasing, its overall treatment still relies heavily on surgical techniques and chemotherapeutics. The targeted therapies that do exist can push development of further genetic/ epigenetic irregularities leading to resistance, metastatic propagation and recurrent disease (Sequist et al., 2011). Identifying suitable treatment strategies from the outset, and monitoring treatment response both throughout and after the course of cancer could be the next step in cancer treatment.

In response to cancer or certain benign conditions, cells of the body may produce specific substances known as tumor markers. These markers may be found in the blood, urine, tumor tissues, stool, or other bodily fluids of patients with cancer. Tumor markers can emerge from both normal cells and cancer cells at any given time; however, in cancerous conditions these substances are observed to be produced at notably higher levels. Thus, many different tumor markers have been studied for clinical use and are currently being used for cancer diagnosis and prognosis. Gene expression patterns and changes to DNA can also be used as tumor markers.

Other tests, such as biopsies, are usually combined with tumor marker measurements to properly diagnose cancer.  With the use of tumor markers, the extent of the disease and/or the patient’s prognosis can be assessed. Additionally, the effectiveness of a treatment and the recurrence of cancer can also be studied using tumor markers. There is currently large number of cancer types and therefore a wide range of tumor markers is currently being studied and used.

Modern serum biomarkers, namely circulating tumor nucleic acids and circulating tumor cells (CTCs), are emerging as novel prognostic or predictive factors (Sturgeon et al., 2008 and McDermott et al., 2011). Scientists working towards the development of these biomarkers to be used in clinical settings will be confronted with the obstacle of choosing the optimal analytical methods among many that have been reported in literature. The best methodology has not been established, however numerous approaches meant to assess the time-related changes of traditional serum tumor marker titers and their prognostic values have been reported.

As biomarker research takes the spotlight, the role of immunohistochemistry within that process is increasing. Please see Novatein Bioscience’s catalog of premier IHC antibodies (link below) for your needs.

Listed below are a few of the tumor markers that have been studied and confirmed to be related to various cancers and are helpful in monitoring stages of disease. Most markers are not used independently, but in combination with additional features such as tumor grade and differentiation status.

Alpha-fetoprotein (AFP) – A major plasma protein encoded by the AFP gene in humans, alpha-fetoprotein (AFP) is a 591 amino acid glycoprotein that is produced by the yolk sac tissues and fetal liver during fetal development. AFP from hepatocellular carcinoma (HCC) displays differential affinity to lectin Lens culinaris agglutinin (LCA) compared to that from chronic hepatitis/liver cirrhosis (Li et al., 2001). Glycoform AFP-L3 has been clinically determined as a highly specific marker for HCC (Leerapun et al., 2007). AFP is used as a tumor marker to diagnose, assess treatment responses, and provide prognosis for liver cancer and germ cell tumors.

Angiostatin – Angiostatin is a 38 kDa fragment of plasminogen, from which angiostatin is produced by autoproteolytic cleavage Angiostatin does not appear to come from a specific gene locus, but is rather seen as a cryptic fragment produced in response to pathologic conditions such as primary tumor growth. Angiostatin is expressed in association with tumor growth and inhibits primary metastatic tumor growth by blocking tumor angiogenesis.

CA-125 –  Also known as carcinoma antigen 125 or MUC16. CA-125 acts as a lubricating barrier due to its glycosylation, and can be found on the ocular surface, respiratory tract, and female reproductive tract epithelia. CA-125 is used as a biomarker to screen for early ovarian cancer and to monitor therapy response in women with ovarian cancer. CA-125 is also used to distinguish between benign and malignant disease in pre- and post-menopausal women presenting with pelvic masses (Felder et al., 2014). However, this ovarian cancer biomarker has limited specificity as elevated CA-125 levels can be found in those without ovarian cancer or those with other cancers.

CA15-3 – Cancer antigen 15-3 (CA15-3) is a protein made by primary breast cancer cells. This protein can be measured in the blood and its levels are higher than normal in most women with metastatic breast cancer. This marker can provide median lead-times of 5-6 months in the early detection of recurrent/metastatic breast cancer. CA15-3 is particularly valuable for treatment monitoring in patients that have disease that cannot be determined using existing radiological procedures. A limitation of this marker is that patient serum levels are rarely elevated in  early or localized disease (Duffy et al., 2010).  

CA19-9 – CA19-9 is a type of antigen released by pancreatic cancer cells and has been extensively studied as a tumor biomarker. CA-19-9 serum levels can provide prognostic, overall survival, and chemotherapy response information as well as predict post-operation recurrence. Poor sensitivity, false negative results, and false positivity of obstructive jaundice limits the CA19-9 serum evaluation (Ballehaninna et al., 2011). CA19-9 is related to the Lewis blood group antigens and only patients belonging to the Le (a-B+) or Le (a+B-) groups will express the CA19-9 antigen. Other cancer types associated with CA19-9 include gallbladder cancer, bile duct cancer, and gastric cancer.

CA72-4 – Biomarker CA72-4 is a glycoprotein found on the surfaces of many malignant cancer cells, including colorectal cancer, ovarian cancer, gastric cancer, and pancreatic cancer with reported sensitivities of up to 50% and overall specificity of over 95% in combination with other known serum markers (Guadagni et al., 1995). It is rarely expressed in benign and normal adult tissues. CA72-4 levels can be measured to determine the extent of the malignancy of the disease.

Carcinoembryonic antigen (CEA) – This glycoprotein is normally found in embryonic entodermal epithelium. Increased levels of CEA may indicate primary colorectal cancer or other malignancies such as medullary thyroid carcinoma and breast, gastrointestinal tract, lung, liver, pancreatic, ovarian, and prostatic cancers. CEA levels can be analyzed in the blood and is mainly used to assess how well treatments are working. 

CYFRA21-1 – Also known as cytokeratin fragment 21-1, this biomarker is clinically useful in prognostication and monitoring in lung cancer. The release of this cytokeratin into circulation may occur because of cellular apoptosis, abnormal mitosis, and spillover from proliferating cells. The CYFRA21-1 biomarker is not suitable for lung cancer screening, but is more useful in clinically assessing the disease stage.

Erythroblastic leukemia viral oncogene homolog 2 (Erb-2, HER2/neu) – The overexpression of oncogenic HER2 is found in 15-30% of primary breast cancers. These proteins have been found to form clusters in cell membranes that may play a role in tumorigenesis.  The HER2/neu biomarker is used as a prognostic and predictive factor for breast cancer. However, the choice for the best method to assess the status of HER2/neu oncogene remains controversial. Tissue-based detection methods by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FSH) are the preferred methods (Masood and Bui, 2002). 

Human epididymis protein 4 (HE4) – This protein is overexpressed in both ovarian and endometrial cancers. HE4 has emerged to be an important biomarker that complements CA125 in selecting between benign and malignant pelvic masses. This biomarker is also used for monitoring response to treatment, and detecting recurrences of both ovarian and endometrial cancer. The expression pattern and potential value of HE4 as a biomarker has been comprehensively reviewed (Li et al., 2009).

Insulin-like growth factor binding protein 4 (IGFBP-4) – IGFBP-4 is a plasma protein and is overexpressed in ovarian cancer patients. Recent findings also show that N- and C-terminal fragments of IGFBP-4 can be utilized as biomarkers for acute coronary syndrome (ACS) patients (Konev et al., 2015).IGFBP-4 has been found to be elevated in early stage disease and significantly elevated in malignant versus benign diseases (Mosig et al., 2012). This protein has also been studied as a biomarker for chronic lupus nephritis (Wu et al., 2016).

Insulin-like growth factor binding protein 5 (IGFBP-5) – IGFBP-5, the most conserved member of the IGFBP family in vertebrates, has been shown to regulate cell proliferation, apoptosis, and play a role in metastasis. This biomarker is used to predict response to therapy and clinical outcome in patients with cancers including retinoblastoma, glioblastoma, adenocarcinoma, breast cancer, prostate cancer, and ER-positive breast cancer.

Mucin-1 glycoprotein (MUC1) – Transmembrane glycoprotein Mucin-1 is aberrantly glycosylated and overexpressed in epithelial cancers, and plays a key role in cancer progression (Nath and Mukherjee, 2014). Overexpression of Mucin-1 is also observed in 90% of breast tumors and therefore is studied as a breast cancer biomarker. Evidence also shows that Mucin-1 can prove to be an effective biomarker for early pancreatic adenocarcinoma (Tinder et al., 2008).

Neuron specific enolase (NSE) – Neuron specific enolase is the cell specific isoenzyme of the glycolytic enzyme enolase. NSE is a highly specific blood-based marker for neurons and peripheral neuroendocrine cells, and is currently the most reliable tumor marker in diagnosis, prognosis, and follow-up of small cell lung cancer (Isgro et al., 2015). NSE is also used as a biomarker for neuroblastoma. 

Prostate-specific antigen (PSA) – PSA is a protein encoded by the prostate-specific gene kallikrein 3 (KLK3) and is produced by normal and malignant cells of the prostate gland. PSA is normally  found secreted in semen with levels in serum; however, increased PSA serum level has been found to represent prostate abnormalities (Presner et al., 2012). The protein is a biomarker that has been widely used to screen men for prostate cancer. However, the inherent limitation to PSA testing relates to the lack of specificity in the screening setting as there is controversy over its suitability and efficacy.

Novatein Biosciences is proud to provide scientists globally with high quality ELISA kits  for detecting and quantifying tumor biomarkers. Our qualified scientists work with integrity and are trained in precision techniques to deliver above satisfactory products into the hands of customers. Please check out our full catalog of biomarker ELISA kits and also our premier IHC antibodies for your needs.

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