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Bio Sensors the New Wave in Cancer Diagnosis.

Bio Sensors the New Wave in Cancer Diagnosis.

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Published by Irv Tololoche

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Categories:Types, Research
Published by: Irv Tololoche on Dec 17, 2011
Copyright:Attribution Non-commercial


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© 2011 Bohuncky and Mousa, publshr and lcns Do Mdcal Prss Ltd. Ths s an Opn Accssartcl hch prmts unrstrctd noncommrcal us, prodd th orgnal ork s proprly ctd.Nanotchnology, Scnc and Applcatons 2011:4 1–10
Nanotechnology, Science and ApplicationsDovepress
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open access to scientifc and medical research
Opn Accss Full Txt Artcl
Bosnsors: th n a n cancr dagnoss
Bran Bohuncky
Shakr A Mousa
Th Pharmacutcal Rsarchinsttut at Albany Collg of Pharmacy and Halth Scncs,Rnsslar, NY, USA;
Collg of Mdcn, Kng Saud Unrsty,Ryadh, Saud ArabaCorrspondnc: Shakr A MousaTh Pharmacutcal Rsarch insttutat Albany Collg of Pharmacy andHalth Scncs, On Dscory Dr,Rnsslar, NY 12144, USATl
1 518 694 7397Fax
1 518 694 7567emalshakr.mousa@acphs.du
The earlier cancer can be detected, the better the chance o a cure. Currently, manycancers are diagnosed only ater they have metastasized throughout the body. Eective, accuratemethods o cancer detection and clinical diagnosis are urgently needed. Biosensors are devicesthat are designed to detect a specic biological analyte by essentially converting a biologicalentity (ie, protein, DNA, RNA) into an electrical signal that can be detected and analyzed. Theuse o biosensors in cancer detection and monitoring holds vast potential. Biosensors can bedesigned to detect emerging cancer biomarkers and to determine drug eectiveness at varioustarget sites. Biosensor technology has the potential to provide ast and accurate detection,reliable imaging o cancer cells, and monitoring o angiogenesis and cancer metastasis, and the ability to determine the eectiveness o anticancer chemotherapy agents. This review will briefy summarize the current obstacles to early detection o cancer and the expanding use o  biosensors as a diagnostic tool, as well as some uture applications o biosensor technology.
biosensor, oncogene, nanotechnology, biotechnology, cancer detection, diagnosis, point-o-care
Cancer is the second leading cause o death in the United States and is expected to claim the lives o nearly 570,000 people in 2010 (http://www.cancer.org/).This number equates to
1500 deaths/day. One in two men will be diagnosed with some orm o cancer over the next year, while or women, the probability o  being diagnosed with cancer is just over 30% (
1 in 3). Cancer can take over 200distinct orms, including lung, prostate, breast, ovarian, hematologic, skin, and colon cancer, and leukemia, and both environmental actors (eg, tobacco smoke,alcohol, radiation, and chemicals) and genetic actors (eg, inherited mutations and autoimmune dysunction) are associated with an increased risk o developing can-cer. Bacterial and viral inections are also strongly associated with some types o cancer (ie, stomach cancers and cervical cancer, respectively). The most commontype o cancer in men and women is prostate and breast cancer, respectively, with192,000 new cases o each reported annually. Although cancer is most commonlydiagnosed later in lie (77% o cases are diagnosed in individuals aged 55 yearsand older),
11,000 cases will be diagnosed in children aged 0–14 years. Notonly is cancer deadly, but it is one o the most expensive diseases in the United States, with total cancer-related expenses in 2008 o approximately $228.1 billion(seehttp://www.cancer.org/).
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This article was published in the following Dove Press journal:Nanotechnology, Science and Applications24 December 2010
Nanotchnology, Scnc and Applcatons 2011:4
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Bohuncky and Mousa
The American Cancer Society (ACS) estimates that theaverage 5-year survival rate or all cancers or the years 1996– 2004 has increased to 66% (up rom 50% or 1975–1977).This increase in survival can be attributed to technologicaladvances resulting in better treatment and improvement inearly diagnosis. However, the 5-year survival or certaincancers such as liver, pancreatic, and lung remains very low(6%–16%). The use o emerging biosensor technology could  be instrumental in early cancer detection and more eectivetreatments, particularly or those cancers that are typicallydiagnosed at late stages and respond poorly to treatment,resulting in improvements in patient quality o lie and overallchance o survival.Cancer is dened as abnormal and uncontrolled cellgrowth due to an accumulation o speciic genetic and epigenetic deects, both environmental and hereditary inorigin. Unregulated cell growth leads to the ormation o atumor mass that over time becomes independent o normalhomeostatic checks and balances. Tumor cells in essence become resistant to apoptosis and other antigrowth deenseswithin the body.
As the cancer progresses, the tumor beginsto spread beyond the site o origin and metastasize to other  body organs and systems, at which point, the cancer isessentially incurable.The two major tumorigenesis mechanisms areactivation o oncogenes and inactivation o tumor sup- pressor genes (TSGs).
Activation o oncogenes occursthrough mutation or duplication o a normal gene (a proto-oncogene) involved in the regulation o cell growth, prolieration, and/or dierentiation. This typically resultsin constitutive activation or excess levels o a normalgene product, leading to the deregulation o cell growth,increased cell division, and tumor ormation. Perhaps moreso than any other type o oncogene, growth actor recep-tors have been investigated as potential cancer biomarkers.The human epidermal growth actor receptor Her-2, or example, is amplied in
33% o all breast cancers, and cancers with amplied Her-2 tend to grow and spread moreaggressively. Thus, knowledge o Her-2 status is critical indetermining the proper course o treatment. Trastuzumab,a recombinant humanized monoclonal antibody directed against Her-2 as targeted therapy or breast cancer, is nowstandard adjuvant treatment or patients with this type o amplied gene expression.
TSGs are involved in the regulation o inappropriatecell growth and prolieration by slowing or stopping celldivision. Three o the most well-studied TSGs in cancer areretinoblastoma protein (Rb), BRCA1/2, and p53.
The Rb isa master regulator o cell division, and mutation o Rb playsa role in many cancers. Point mutations and deletions are themost common causes o inactivation o the Rb1 gene.
 BRCA1 is a DNA repair enzyme, which is involved in‘prooreading’ newly replicated DNA or delity and pres-ence o mutations. DNA repair enzymes normally unc-tion to remove replication errors beore the cell divides.BCRA1 gene mutations account or about 50% o heredi-tary breast cancers and 80%–90% o hereditary breast and ovarian cancers.
Finally, the p53 protein is a master regulator o apoptosis or programmed cell death. Mutationsin p53 are ound in brain, breast, colon, lung, hepatocel-lular carcinomas, and leukemia. Another major concernwith the loss o p53 is that it can serve as a mechanism o chemotherapeutic drug resistance.
The developmento biosensors that can detect the presence o mutations in p53, Rb, and BRCA1 is o great importance in terms o  being better able to determine cancer susceptibility as wellas more accurate prognosis and treatment regimens.
Cancer biomarkers
The National Cancer Institute (NCI) denes a biomarker as “a biological molecule ound in blood, other bodyfuids, or tissues that is a sign o a normal or abnormal process or o a condition or disease. A biomarker may beused to see how well the body responds to a treatment or a disease or condition”.
Biomarkers can be o variousmolecular origins, including DNA (ie, specic mutation,translocation, amplication, and loss o heterozygosity),RNA, or protein (ie, hormone, antibody, oncogene, or tumor suppressor). Cancer biomarkers are potentiallyone o the most valuable tools or early cancer detection,accurate pretreatment staging, determining the responseo cancer to chemotherapy treatment, and monitoring dis-ease progression.
Biomarkers are typically detected inhuman fuids such as blood, serum, urine, or cerebral spinalfuid, but they can also be present in or on tumor cells.
 A partial list o tumor biomarkers is presented in Table 1.Most o these biomarkers, however, have yet to demonstratesucient sensitivity and specicity or translation intoroutine clinical use or or treatment monitoring. This isan area that biosensor technology can potentially improveupon. Discussion o some o the major cancer biomarkersis presented below.
Prostate-specifc antigen
Prostate-specic antigen (PSA) was one o the rst tumor  biomarkers to be identied and put into routine clinical use
Nanotchnology, Scnc and Applcatons 2011:4
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Bosnsors and arly cancr dtcton
or screening and diagnosis o prostate cancer. Studies haveshown that above-normal PSA levels correlate directly with prostate cancer. A normal level o PSA is 4.0 ng/mL. A studyconducted by Smith ound that roughly 30% o men with aPSA level between 4.1 and 9.9 ng/mL had prostate cancer.
 In addition to prostate cancer, elevated PSA levels may alsoindicate benign prostatic hyperplasia, prostatitis (infamma-tion o the prostate), or smaller tumors that do not prove to beatal. Thus, PSA levels are not always indicative o malignanttumors, a act that has prompted considerable controversyabout the value o routine PSA screening or prostate cancer.Small tumors that are detected by PSA screening may inact grow so slowly that death rom the tumor would not be possible in a man’s lie span. Furthermore, treatment o these slow-growing tumors is costly and oten involves lie-changing surgeries that may not be necessary. However, ina study o 695 men with prostate cancer who were assigned to either radical prostatectomy or observation (watchulwaiting), it was shown that prostatectomy reduced morbidity,mortality, the risk o metastasis, and local progression morethan watchul waiting,
suggesting that treatment o any kind is more valuable than simple observation. Thus, despite thecontroversy surrounding PSA screening, it may be less harm-ul or a patient to receive unnecessary treatment or a benigncondition than to not be treated or a malignant tumor.Another issue with the PSA test is that alse positivesare common, and many men with elevated PSA levels donot have prostate cancer at all.
This tendency with PSAscreening is an area that biosensors can help by eliminatingsome o the ambiguity surrounding the common screeningmethods used today.
Cancr antgn 125
Elevated cancer antigen (CA) 125 is most commonlyassociated with ovarian cancer and is also linked to cancerso the uterus, cervix, pancreas, liver, colon, breast, lung,and digestive tract. Several nonpathological conditions suchas menstruation and pregnancy can also result in increased levels o CA 125.
CA 125 is elevated in 90% o womenwith advanced ovarian cancer and in 40% o patients withintra-abdominal malignancy. However, it should also benoted that in Stage 1 ovarian cancer, 50% o patients willhave normal CA 125 levels.
Other biomarkers that arelinked to ovarian cancer are germ cell in origin such ashuman chorionic gonadotrophin (HCG), alpha-etoprotein(AFP), and lactate dehydrogenase (LDH).
Elevated CA 125ollowing total abdominal hysterectomy or bilateral salpingo-oophorectomy, which may ollow rst-line chemotherapytreatment, is suggestive o disease recurrence or treatmentailure. In addition, increases in CA 125 have been used toidentiy the progression o benign cells to malignant cells.
 Overall, CA 125 is a valuable biomarker not only or can-cer diagnosis, but also or various other aspects o cancer treatment and progression.
CA 15-3
CA 15-3 is an important biomarker analyzed in breast cancer  patients. Other biomarkers that are linked to breast cancer are carcinoembryonic antigen (CEA), BRCA1, BRCA2, and CA 27.29.
CA 15-3 is used clinically most oten to moni-tor patient therapy in cases o advanced breast cancer.In patients with breast cancer, it has been shown that CA 15-3concentrations increase by 10% in Stage I cancer, 20% inStage II, 40% in Stage III, and 75% in Stage IV breastcancer.
Tampellini and colleagues investigated the relation-ship between CA 15-3 levels and breast cancer and showed that individuals with values o 
30 U/mL beore treatmentonset had signicantly higher survival times than individualswho had higher levels. The study also ound that higher CA 15-3 values correlated with extensive metastasis.
 Another study determined that rising CA 15-3 values ater treatment can indicate disease recurrence.
At present,CA 15-3 levels are considered along with tumor size, cancer stage, and negative risk actors (ie, Her-2 and ER/PR status)in determining treatment protocols. Other conditions that cancause CA 15-3 levels to increase are endometriosis, pelvicinfammatory disease, hepatitis, pregnancy, and lactation.
Cancr-tsts antgns
Cancer-testis (CT) antigens are a unique class o cancer  biomarker. They are highly expressed in many tumors, butnot in normal cells, except or germ cells o the testis. Thus,they have been heavily pursued as potential immunogenictargets or cancer immunotherapies (ie, cancer vaccines), and 
Table 1
Common bomarkrs utlzd for cancr dtcton
Type of cancerBiomarke
BrastBRCA1, BRCA2, CA 15-3, CA 125, CA 27.29, CeA,NY-BR-1, iNG-1, HeR2/NeU, eR/PRColonCeA, eGF, p53esophagalSCCLrAFP, CeALungCeA, CA 19-9, SCC, NSe, NY-eSO-1MlanomaTyrosnas, NY-eSO-1OaranCA 125, HCG, p53, CeA, CA 549, CASA, CA 19-9,CA 15-3, MCA, MOv-1, TAG72ProstatPSA

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