BIO-MARKERS AND BIO-SENSORS: UNRAVELLING THE MAJOR MECHANISTIC INTERVENTIONS IN CANCER PROGNOSIS

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ABOUT AUTHOR
Rajesh Tiwari
Junior Technical Assistant
Pharmaceutical Science and Natural Products
Central University of Punjab, Bathinda
rajesh.tiwari851@gmail.com

ABSTRACT
Biosensors are a tool that combines the biochemical element with a transducer that generates an indication for the identification of disease. Numbers of biosensors are used in different medical application. Biomarker and Biosensors play an important role for early stage exposure of cancer. It is a cost-effective, increased assay speed, resiliency, the ability for multi-target analysis method. Genomic and proteomic molecular tools are also used for the exposure of tumors. These methods produce a molecular mark that provides a new opening for utilizing biosensors and biomarkers. As with many disease conditions, it is not easy to find exact and responsive markers that are associated with only one marker. Different numbers of molecular signatures are used for the diagnosis of cancer, such as proteins, peptides, over expression gene and gene mutation. This review provides a general idea of the biosensors and biomarkers technology that is currently developed and researched for cancer markers and diagnosis.

INTRODUCTION
Cancer testing in the human body is tough. It is consists of more than two hundred dissimilar disease and distressing some humans organs^[1]. nonstop cell division characterizes cancer cells. Metastasis of cancer cell to different healthy organs, self-cell division, the death of healthy cells, continuous formation of new blood vessels^[2]. Cancer is  the main reason of death in developed and developing countries. The largest cause of death result as of the prostate (males), pancreas, breast (females), colon, lung^[3]_.

When emergent biosensors for cancer testing, it is important to well-known about the difficulty and some basic thing about cancer^[3]. Cancer is the result of disruption of the normal cell signaling pathway, produce cancer cells^[4]. The genetic disease can cause cancer. In genetic it is a modification of DNA sequence of keygenes, and it changes the protein composition of tumor of cells. As DNA sequence changes, the cell’s behavior becomes deregulated and produces cancer cells. Environmental factors such as lifestyle, diet, ultraviolet radiation^[3].

Cancer detection
Early diagnosis of cancer generates more chance for survival of the patient. For successful early diagnosis of cancer, specific methods are required^[4]. Advance development in molecular biology is opening many ways for early stage cancer diagnosis.  Since cancer cells development generates many signals and shows many changes.  This information can be used for the diagnosis and cure of the patient^[3]. Innovative biosensor techniques are playing a great role for identification of early stage cancer^[5]. In this review article, I will talk about the different type of biosensors for clinical testing, diagnosis.

Cancer Biomarkers
Cancer antigens are used as biomarkers for cancer diagnosis. This cellular molecule can be detected in cancer cells, urine, blood or other body fluid that are expressed due to cancer cell growth. There are many ranges of biomarkers that are well-known with a different type of cancers (Table.1). These biomarkers include DNA modification, RNA, proteins, hormones, a molecule of the immune system and other related molecules. Thus, multiple antigens can be identified and used as biomarkers for cancer identification and diagnosis. Some genes are identified for specific cancer that can be used for diagnosis of cancer. Ex. The breast cancer antigens NY-BR-1 and ING-1 was tested by the use of cancer testing antigens CAGE-1 and ESO-1. In the following table, cancer type disease associated with different known biomarkers^[6].

Table -1:Various cancer and their specific biomarkers

PSA(Prostate-specific antigen)Bio-marker
Prostate cancer is common cancer in men in developed and developing countries. Prostate-specific antigen (PSA) is a biomarker for the identification of prostate cancer in the male. It is the type of solid tumor, which has clinical useful protein biomarkers for diagnostics^[1]. PSA has exposed sensible sensitivity for detection of early cancer^[7]. Most of the men  who diagnosed with prostate cancer are dying for other reasons. Most of the prostate cancer is clinically diagnosed while another prostate cancer is as such remaining over the year. All prostatic cancer patients develop a biochemical change that changes in a clinical diagnosis and finally causing death. PSA is a suitable biomarker for the detection of prostate cancer. PSA detection for prostate cancer in men is very complicated. The cutoff level of PSA in blood is four ng/ml for the detection of prostate cancer. High level (between 4 ng/ml to 10 ng/ml) of PSA in blood is not a cause of prostate cancer. While the presence of PSA < 0.5ng/ml may cause of prostate cancer.Thus, PSA for detection of prostate cancer is not reliable^[8].

CEA (Carcinoembryonic antigen) andCarbohydrate Antigen 19-9 (CA 19-9) Bio-marker
CEA (Carcinoembryonic antigen) is a proteomics-based biomarker^[9]. It is associated with progression of the colorectal tumor^[10]. CEA is a detected in the presence of gastrointestinal tract cancer. CEA is detected when thelevel is more than 5ng/ml in blood. CEA is elevated only in the presence of CRC (colorectal carcinoma) in most of the patient. Carbohydrate Antigen 19-9 (CA 19-9) is present in gastrointestinal tract cancer, and it is a type of glycoprotein with high molecular weight. It was detected in human blood. Carbohydrate Antigen 19-9 (CA 19-9) is utilized for the diagnosis of pancreatic, gastric, and colorectal cancer^[11].

Cancer Bio-sensors
The use of biosensors for the detection and solve the problem of cancer is a sensitive, fast and cheap measurement tools. IUPAC has defined the biosensors, but theexact definition was given by the Newman et al. (2004). They define as ‘a compact analytical device incorporating a biological derived sensing element either integrated within or intimately associated with a physicochemical transducer’. The first biosensors were acatalytic system that was enzymes with the transducer. The transducer converts that biological response into an electrical signal. In these days, next-generation biosensors are available that works in association with antibodies and receptors^[12].

Biomarkers are an indicator of normal biological processes, pathogenic processes or pharmacologic response to a therapeutic intervention. Cancer biomarkers are themolecular change that can be detected in the urine, blood, cancer cells and other body fluid of cancer patient. Cancer biomarkers work on the basis of DNA modification, RNA, protein modification and in the presence of other biological molecules (Table.2)^[3]. Biosensors are a point-of-care device that can be used for analyzing the clinical cancer sample at home or in doctor’s surgery. For the development of specific biosensors, specific markers need to be identified to ensure specificity of the device. Biosensors can provide a multi-array sensors system for multi-marker diagnosis. It is an advanced platform for the multi-analyze testing system, for a cancer diagnosis^[6]. In the following table, cancer type disease associated with different known biosensors.

Table -2: Cancer types associated with different known biosensors and their principle

Biosensors in cancer disease

Biosensors for the detection of PSA (Prostate-specific antigen) Bio-mark
On aglobal scale, prostate cancer has achief health issue, and it is a third common cancer in men. PSA (Prostate-specific antigen) is biomarkers to screen prostate cancer patient, and it is an important marker for the detection of early-stage prostate cancer^[6]. PSA is found in human serum, either in free form or in combined with various protease inhibitors. The level of 10 ng/ml or higher PSA is a probable indicator for prostate cancer. The intensity of PSA greater than four ng/ml in serum is an indicator for the biopsy. Testing of PSA is veryexpensive and time-consuming^[12].

Biosensor for the Detection of CEA (carcinoembryonic antigen) Biomarker
Breast cancer is the most common cancer in women and leading cause of death in women. Due to improvement in detection and diagnosis has decreased the death rate. For early detection of breast cancer in women, a bio-mark signal is used^[13].  Carcinoembryonic antigen(CEA) is a well-known biomarker that is associated with progression of colorectal tumors. An immune sensor for determination was prepared by positively charged toluidine blue (TB) coated on negatively charged poly-sulfanilic acid (PSAA) customized glassy carbon electrode (GCE). The prostate-specific antigen can be identified by the use of electrochemical detection of colloidal gold/alumina solution. In prostate-specific antigen, a potential change occurs before and after the antigen-antibody interaction^[10].

Biosensor for the Detection of CA 125 (cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) Biomarker
CA 125 is also known as mucin 16 or MUC 16. MUC 16 is a protein that is identifying in a human being by the use of MUC 16 genes. CA 125 is a tumor marker or biomarker that is present in the blood of patients with aspecific type of cancer. CA 125 is used as the marker for ovarian cancer. Enzymatic activity of the protein can be used as the biomarker for cancer activity. Ex-telomerase that activity is regulated in malignant tumors^[3]. Proteomics approaches have been used to generate protein expression of the normal breast cell that compared with the cancer cell of the breast^[3].

Biosensorsfor the detection of AFP (Alpha-Fetoprotein) Bio-mark
AFP (Alpha-Fetoprotein) is a widely used as a tumor marker for germ cell tumor and hepatocellular carcinoma. An immunosensor based AFP was prepared by the entrapping reaction of thionine (is a metachromatic dye that is used for biological staining) into Nafion (this is an engineering based polymer used in preparation of enzyme-based sensors) to form a composite of Thi/Nf membrane. This membrane is a borderline that contain amine group inassembling with gold nanoparticle layer to check the alpha-fetoprotein antibody. For detection of AFP, a new enzyme immune sensors has developed. This enzyme immune sensorwas developed with layer by layer assembly of gold nanoparticle and thionine immobilized on the Nafion-modified electrode surface by electrostatic adsorption^[10].

Simultaneous multi-marker detection
There is multi-cancer marker are available in the market, in this a multi-ELISA(multi-analyte enzyme-linked immunosorbent) assay kit is used on the same chip to detect several analytes at the same time by the using immunogens principle. A simple development for disposable electrochemical immune sensor for simultaneous determination of CA19-9 and CA125^[4].

Biosensorsfor the detection of AFP (Alpha-Fetoprotein) Bio-mark
AFP (Alpha-Fetoprotein) is a widely used as a tumor marker for germ cell tumor and hepatocellular carcinoma. An immunogens based AFP was prepared by the entrapping reaction of thionine (is a metachromatic dye that is used for biological staining) into Nafion (this is an engineering based polymer used in preparation of enzyme-based sensors) to form a composite of Thi/Nf membrane. This membrane is a borderline that contain amine group inassembly with gold nanoparticle layer to check the alpha-fetoprotein antibody. For detection of AFP, a new enzyme immune sensors has developed. This enzyme immune sensor was developed with layer by layer assembly of gold nanoparticle and thionine immobilized on the Nafion-modified electrode surface by electrostatic adsorption^[10].

Transducer
A biosensors is a bio-analytical device (ex tissue, microorganism, cell organelles, cell receptors, enzyme, antibodies, nucleic acid etc) which is very closely related with physicochemical transducer or transducing microsustem^[4]. The transduceris a biological component that convert thebiological  response into ameasurableelectronic signal^[12]. The transducers used in biosensors are optical, thermometric, piezoelectric and magnetic. Amperometric and potentiometric transducers are most commonly used in conjunction with electrochemical biosensors. Thus, some transducer method is possible for the development of biosensors technology^[14] Electrochemical sensors measure the electrochemical changes that occur on the surface of detecting electrode when analytes interact with a sensing surface.  The electrochemical test is simple, reliable and low detection limit. The electrical change can be potentiometric (a change in the measured voltage between the indicator and reference electrodes),  or amperometric (a change in the measured current  of applied voltage) or conductometric (a change in the transport charge). An optical transducer is used to determine the affinity reaction of antigen- antibody and DNA interaction^[15].

Electrochemical transducer
Electrochemical biosensors are portable, simple, easy to use, cost-effective and disposable. It is a small pocket size device that make applicable for home use and in the doctor’s surgery. The glucose biosensors arethe best example of electrochemical biosensors. This is widely used throughout the world for glucose testing in the home and at the site and one important thing this is a hand held device that is combining with several electrochemical biosensors on a single chip. This is used for multiple electrolyte systems. For cancer biomarkers, analysis a bio-affinity based electrochemical biosensors are used to determine the gene mutation of biomarkers and protein biomarkers. Electrochemical-basedbio-sensors for cancer detection based on DNA hybridization and for gene mutation detection. In this device, a single standard DNA is placed on theelectrode surface and when DNA hybridization takes place than detection conduct in the presence of a number of methodologies^[6]. Wang and Kawde used a chronopotentiometric transduction for electrochemical detection of mutation related to the breast cancer genes BRCA1 (BReastCAncergene one) and BRCA2 (BReastCAncergene two. Tansil et al. use the catalytic oxidation of the guanine nucleobase for the detection of cancer marker genes from breast tissue. Protein biomarkers are more widely used for cancer analysis. For detection principle, change in electrochemical properties on the sensor surface due to the antibody antigens interaction is used. Faradic impedance spectroscopy has been reported for the CEA biomarkers analysis. In this gold nanoparticle modified glassy, carbon electrode is used^[5].

Optical transducer
Optical transducer based on the method of internal reflectance spectroscopy, surface Plasmon resonance and evanescent wave sensing. In this light passes through optical fibers towards sensing surface and reflected back again. The measured optical signals often include absorbance, fluorescence and surface plasmon resonance. Optical biosensors are mainly used for screening a large number of samples.Manly fluorescence labels are used for the detection. An Affymetrix gene chip is used for the cancer gene identification^[6]. Other biosensors such as grating couplers, resonance mirrors, and surface plasmon are used for the cancer biomarkers diagnosis. Surface plasmon system such as BiaCoreTM biosensor chip is a most widely used optical transducer for biosensor platform. These systems are also applied for other application rather than biomarkers detection. Different surface plasmon resonances have been developed for cancer marker detection. These sensors are more suitable for laboratory-based testing rather than apoint of care device for onsite analysis^[16].

Mass-sensitive transducer
Mass-sensitive transducer technology is also a label-free technology. Piezoelectric immune sensors are widely used for the detection of cancer markers where the specific antibody is immobilized on the sensors chip. There are some devices available on the market, which is based on this technology. One best example is QCMA-1 (quartz crystal microbalance)sensors that are fully automated^[17]. This technique is based on the use of gold chip with antibody immobilized on the surface of the sensors. In these days, microcantilever-based sensors are widely used for cancer detection (Figure.1). In microcantilever, affinity interaction works between the antibody on the surface of the cantilever and the biomarkers are detected through the amount of bending of the sensors due to mass change in the resonance frequency^[18].

Figure.1 Schematic representation of biosensor containing the biorecognition element, transducer and the physical output whose level iscorrelated to the concentration of the analyte of interest

CONCLUSION
Cancer testing and diagnosis is very typical task yet new development in physical science and engineering science has opened the new way of clinical testing and diagnosis in thefield of cancer. Development of molecular tools on the basis of gene expression, protein profile, and protein post-translation modification has opened the new way for utilization of biosensors for cancer testing. The use of biosensors for cancer clinical testing may increase assay speed and flexibility, multi-target analyzes and automation has reduced the cost of cancer testing and diagnosis.

Acknowledgments
I am very thankful to Prof. R. K. Kohli, Vice Chancellor, Prof. P. Ramarao, Dean Academic Affairs and Dr. Raj Kumar, Assistant Professor & OIC, Central University of Punjab, Bathinda for their continuous encouragement and support.

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