CANCER BIOMARKERS

Cancer biomarkers can be used for prognosis: to predict the natural course of a tumor, indicating whether the outcome for the patient is likely to be good or poor (prognosis). They can also help doctors to decide which patients are likely to respond to a given drug (prediction) and at what dose it might be most effective (pharmacodynamics). Cancer biomarkers are present in tumor tissues or serum and encompass a wide variety of molecules, including DNA, mRNA, transcription factors, cell surface receptors, and secreted proteins. One of these serum biomarkers in wide use is PSA which is produced by normal prostate cells. The higher the PSA is in the serum, the higher the correlation is toward the existence of prostate cancer.

Prognostic biomarkers allow the natural course of a tumor to be predicted, distinguishing ‘good outcome’ tumors from ‘poor outcome’ tumors, and they guide the decision of whom to treat (or how aggressively to treat). Predictive biomarkers are used to assess the probability that a patient will benefit from a particular treatment. For example, patients with breast cancer in which the gene encoding the oestrogen receptor is expressed respond to treatment with tamoxifen, whereas when the gene ERBB2 (also known as HER2) is amplified in the tumour, the patients benefit from treatment with trastuzumab (Herceptin) instead. Pharmacodynamic biomarkers measure the near-term treatment effects of a drug on the tumor (or on the host) and can, in theory, be used to guide dose selection in the early stages of clinical development of a new anticancer drug.

The application of cancer biomarkers is still controversial. PSA is a widely used cancer biomarker. However, there are reasons other than cancer that can cause rises in PSA, such as infections within the prostate gland, increased exercise with irritation of the affected area, and even vigorous physical examination by a doctor. Cancer antigen 125 (CA-125) can be a biomarker of ovarian cancer risk or an indicator of malignancy, but it has low sensitivity and specificity. Levels of this marker can be high in people who have pancreatitis, kidney or liver disease, making its accuracy as a cancer diagnostic tool very limited. Carcinoembryonic antigen (CEA) is another biomarker that is elevated in patients with colorectal, breast, lung, or pancreatic cancer. As a screening test, it can be elevated by many other factors than cancer; smoking for instance raises CEA levels.

An ideal tumor marker should be measured easily, reliably and cost-effectively using an assay with high analytical sensitivity and specificity. In addition, an ideal tumor marker should be present in detectable quantities at early or preclinical stages and the quantitative levels of the tumor marker should reflect tumor burden. Recent technological advances, especially in the fields of genomics and proteomics, have made it easier to identify many biomarkers at once in high-throughput screens. The validation of cancer biomarkers - that is, determination of clinical relevance and applicability - is also quite challenging, and many questions have been raised regarding how new tests will be developed, evaluated, and integrated into clinical practice

Cancer biomarkers in clinical trials

Protein Name	Alternative Name	Biochemical Class/Role
HER2	ErbB2, NEU, CD340	A type I membrane glycoprotein belonging to the EGF receptor family. Despite of unable to directly bind growth factors, HER2 forms a heterodimer with other ligand-bound EGF receptor family members, helping stabilize ligand binding and enhance kinase-mediated activation of downstream molecules. HER2 can be used in prognosis of numerous carcinomas, including breast, prostate, ovarian, lung cancers and so on.
PSA	Kallikrein 3, KLK3	Prostate-specific antigen (PSA) is a protein produced by the cells of the prostate gland. PSA is normally present in small quantities in the serum, and is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer.

Putative Cancer Biomarkers

Protein Name	Alternative Name	Biochemical Class/Role
aFGF	FGF-1, ECGF	A member of the fibroblast growth factor family. aFGF binds to four high affinity cell surface receptors (FGFR1–4) and shows a wide range of endocrine-like activities. As a multiple function growth factor, aFGF is involved in many processes, such as embryonic development, morphogenesis, angiogenesis, wound healing and atheromatosis, carcinogenesis, development, and invasion of cancer
Aurora A		A mitotic serine/threonine kinase that is integral for healthy cell proliferation. Aurora A is activated by one or more phosphorylations and its activity peaks during the G2 phase to M phase transition in the cell cycle
Bcl-2		Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial outer membrane permeabilization (MOMP) and can be either pro-apoptotic or anti-apoptotic. There are a total of 25 genes in the Bcl-2 family known to date. The Bcl-2 gene has been implicated in a number of cancers, including breast, melanoma, prostate, and lung carcinomas, as well as autoimmunity and schizophrenia.
bFGF	FGF-2	A member of the fibroblast growth factor (FGF) family appears to be involved in remodeling damaged tissue. bFGF is a heparin-binding cationic protein involved in a variety of pathological conditions including angiogenesis and solid tumour growth.
Carbonic Anhydrase IX	CAIX, CA9	A member of the carbonic anhydrase (CA) family involved in cell proliferation and cellular transformation. CAIX is involved in tumorigenesis through many pathways, such as pH regulation and cell adhesion control.
Cathepsin D	CTSD, CLN10, CPSD	An lysosomal aspartic protease that depends critically on protonation of its active site Asp residue and gets activated at pH 5 in endosome of hepatocytes where it degrades insulin. Mutations in the CTSD gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease.
CD24		A cell adhesion molecule, expressed at the surface of most B lymphocytes and differentiating neuroblasts. CD24 is anchored via a glycosyl phosphatidylinositol link to the cell surface
CD31	PECAM-1	A transmembrane glycoprotein expressed by endothelial cells, platelets, monocytes, neutrophils, and certain T cell subsets that plays a key role in removing aged neutrophils, tissue regeneration, neutrophil recruitment in inflammatory responses, transendothelial migration of leukocytes, as well as in cardiovascular development. CD31 is also expressed in certain tumors, including epithelioid hemangioendothelioma, other vascular tumors, and histiocytic malignancies.
CD38	T10	A glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B and natural killer cells, which functions in cell adhesion, signal transduction and calcium signaling. CD38 has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
CD74	DHLAG, HLADG	A transmembrane protein expressed on antigen presenting cells, the invariant chain of class II MHC. CD74 is upregulated in several cancers and is also expressed by non-immune cells during inflammation
CD146	MCAM, MUC18	A Ca2+-independent cell adhesion molecule belonging to the immunoglobulin superfamily, involved in heterophilic cell interactions. CD146 triggers tyrosine phosphorylation of FYN and PTK2 and subsequently induced signal transduction, proteolysis, or immune recognition. CD146 is also expressed on metastatic lesions and advanced primary tumours, and thus has been suggested to play an important role in tumour progression and metastasis.
CD147	EMMPRIN, BSG	A transmembrane glycoprotein belonging to Ig superfamily, which induces the production and release of matrix metalloproteinases (MMP) in the surrounding mesenchymal cells and tumor cells, and thereby promotes invasion, metastasis, growth and survival of malignant cells. CD147 displays increased expression in many cancers, and it has been previously demonstrated to participate in cancer metastasis and progression.
CD208	DC-LAMP, LAMP3	Dendritic cell-lysosomal associated membrane protein, a member of the lysosomal associated membrane protein (LAMP) family, specifically expressed by human DCs on activation. Overexpression of CD28 promotes metastasis in uterine cervical cancer.
CEACAM1	CD66a	A member of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin superfamily. CEACAM1 mediates cell adhesion via homophilic as well as heterophilic binding to other CEA cell adhesion molecules. It plays a role in a variety of biochemical processes, including the differentiation and arrangement of tissue three-dimensional structure, angiogenesis, apoptosis, tumor suppression, metastasis, and innate and adaptive immune responses.
CEACAM5	CD66e	A member of the carcinoembryonic antigen (CEA) gene family. CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
CEACAM6	CD66c	A member of the carcinoembryonic antigen (CEA) gene family. CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
E-Cadherin	CDH1, CD324	A classical cadherin from the cadherin superfamily with calcium-dependent activity. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis.
ECM1		A secreted glycoprotein, playing a pivotal role in endochondral bone formation, angiogenesis, and tumour biology. ECM1 is significantly elevated in many malignant epithelial tumors and is suggested as a possible trigger for angiogenesis, tumor progression and malignancies. It may also regulate endochondral bone formation, skeletal development and tissue remodeling.
EGF		A growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR. Salivary EGF, which seems also regulated by dietary inorganic iodine, also plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity.
EGFR	HER1, ErbB1	A type I transmembrane glycoprotein that binds EGF as well as several other EGF family lagands. Binding of a ligand induces EGFR protein homo- or heterodimerization, the subsequent tyrosine autophosphorylation and initiates various down stream pathways (MAPK, PI3K/PKB and STAT).
EpCAM	TROP-1, TACSTD1, CD326	A pan-epithelial differentiation antigen that is expressed on almost all carcinomas. EpCAM functions as a homotypic calcium-independent cell adhesion molecule. It is being used as a target for immunotherapy treatment of human carcinomas.
ErbB4	HER4	A receptor tyrosine kinase belong to the EGF receptor subfamily. Lingands of ErbB4 include neuregulins-2 and -3, heparin-binding EGF-like growth factor and betacellulin. Ligand binding induces a variety of cellular responses, such as mitogenesis and differentiation.
FAP
FGFR3	CD333	A member of the fibroblast growth factor receptor family, of which amino acid sequence is highly conserved between members and throughout evolution. Defects in the FGFR3 gene has been associated with several conditions: achondroplasia, bladder cancer, thanatophoric dwarfism and seborrheic keratosis.
FOLR2	FR-P3	A member of the folate receptor (FOLR) family, of which members have a high affinity for folic acid and for several reduced folic acid derivatives, and mediate delivery of 5-methyltetrahydrofolate to the interior of cells.
Galectin-3		Galectin-3 is a member of the lectin family and is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space. Galectin-3 has broad biological functionality. Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations. It has also been demonstrated to be involved in cancer, inflammation, stroke, and fibrosis.
Glypican 3	GPC3, OCI-5	A heparan sulfate proteoglycan anchored to the membrane, expressed at a markedly elevated level in hepatocellular carcinoma. Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers
HCG	CGA	Human chorionic gonadotrophin (HCG) is a glycoprotein hormone produced in pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast. HCG is also produced by some kinds of tumor, and is an important tumor marker especially (with clinical significance) in Gestational trophoblastic disease.
HER3	ErbB3	A member of the EGFR family of receptor tyrosine kinases. HER3 forms heterodimers with other EGFR family members and initiate signaling related to cell proliferation or differentiation. Amplification of HER3 gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors.
HGFR	c-MET	Receptor for the hepatocyte growth factor (HGF). Normal HGF/HGFR signaling is essential for embryonic development, tissue repair or wound healing, whereas aberrantly active HGFR has been strongly implicated in tumorigenesis, particularly in the development of invasive and metastatic phenotypes.
HPGD	5-PGDH	A member of the short-chain dehydrogenases/reductases (SDR) family. HPGD is down-regulated by cortisol, dexamethasone and betamethasone or in colon cancer, while up-regulated by TGFB1. Defects in HPGD are the cause of primary hypertrophic osteoathropathy autosomal recessive (PHOAR), cranioosteoarthropathy (COA), and isolated congenital nail clubbing.
IGF1R	CD221	A receptor tyrosine kinase expressed in all cell types and tissues. IGF1R is activated through binding to IGF1 and 2 ligands or by the activity of the Src tyrosine kinase, and subsequently initiates an intracellular signaling cascade (MAPK). It is commonly overexpressed in most malignant tissues including breast, prostate, and pancreas, and affects cancer cell proliferation, adhesion, metastasis and survival by mediating the anti-apoptotic pathway.
IGFBP3		IGFBP3 forms a ternary complex with IGF1 or IGF2, and thus alter the interaction of IGFs with their cell surface receptors. IGFBP3 can leads to apoptosis dependent or independent of the IGF-IGF receptor axis, accordingly acts as a negative regulator of tumorigenesis and progression of certain carcinomas. It also plays a role in neurological disease processes by its interaction with the Alzheimer's survival peptide humanin (HN).
IL-6		A multifunctional α-helical cytokine secreted by a variety of cell types, which is known particularly for its role in the immune response and acute phase reactions. IL-6 exerts actions through forming the complex with IL-6R and glycoprotein 130. It is also involved in hematopoiesis, bone metabolism, and cancer progression.
Kallikrein 6	KLK6	A member of the kallikrein subfamily of serine proteases. Kallikrein 6 has been found to generate amyloidogenic fragments from the amyloid precursor protein, suggesting a potential for involvement in Alzheimer's disease.
L1CAM	CD171, NCAM-L1	A transmembrane cell adhesion molecule belonging to the Ig superfamily, primarily expressed on projection axons of the central nervous system and peripheral nervous system, as well as on a few non-neuronal cell types. L1CAM may play a role in a variety of processes integral to the development of the nervous system, including neuronal migration, neurite outgrowth, and axon fasciculation. L1CAM is also overexpressed in a variety of human carcinomas and is associated with bad prognosis.
Leptin	LEP	One of the most important adipose-derived hormones, secreted mainly by adipocytes, stomach and placenta. leptin is identified as a metabolic and neuroendocrine mediator, and functions in a variety of biological processes including glucose metabolism, immune and inflammatory responses, bone mass regulation, as well as normal sexual maturation and reproduction. Leptin deficiency is implicated in severe obesity, morbid obesity with hypogonadism and impaired cell-mediated immunity.
LKB1
Matriptase	ST14	Matriptase, also known as suppression of tumorigenicity 14 (ST14) is a type II transmembrane serine protease expressed in most human epithelia, where it is coexpressed with its cognate transmembrane inhibitor, HAI-1. Matriptase and HAI expression are frequently dysregulated in human cancer. Matriptase may play a role in cancer invasion, and metastasis.
MIF		Macrophage migration inhibitory factor (MIF) may be involved in cell-mediated immunity, immunoregulation, and inflammation
MMP-2		A member of the matrix metalloproteinase (MMP) family that are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. MMP-2 plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response. Mutations in MMP2 gene have been associated with Torg-Winchester syndrome.
MMP-3	Stromelysin-1	MMP-3 is a member of the MMP family and is thought to be involved in wound repair, progression of atherosclerosis, and tumor initiation
MMP-9	CLG4B	Also known as 92-kDa gelatinase B/type IV collagenase, secreted from neutrophils, macrophages, and a number of transformed cells. MMP-9 degrades various substrates including gelatin, collagen types IV and V, and elastin. It plays control roles in IL8-induced leukocytosis and stem cell mobilization, and is involved in a variety of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.
NEK2
Osteopontin	OPN, BSP-1, SPP1, ETA-1	An extracellular structural protein expressed in bone as well as in other tissues. Osteopontin plays a role in bone remolding through anchoring osteoclasts to the mineral matrix of bones. It is also reported to act as a multifunctional modulator of immune responses. Manipulation of plasma Osteopontin levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.
p21	CDKN1A	p21, also known as cyclin-dependent kinase inhibitor 1, binds to and inhibits the activity of cyclin CDK2 or CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. p21 mediates the resistance of hematopoietic cells to an infection with HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus
p53		p53 is a tumor suppressor protein that works through several mechanisms, such as inducing growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition, activating DNA repair proteins when DNA has sustained damage, or initiate apoptosis
PAI-1	SerpinE1	Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) protein that is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA).
PDGFRA	CD140a	A tyrosine kinase receptor for members of the platelet-derived growth factor family, probably involved in kidney development
PRMT1		A member of the protein arginine methyltransferases (PRMTs) family. PRMT1 is highly mobile both in the cytoplasm and the nucleus. Inhibition of methylation leads to a significant nuclear accumulation of PRMT1. It plays an important role in numerous cellular processes. PRMT1 has also been identified as an essential component of mixed lineage leukemia (MLL) oncogenic complexes, revealing its potential as a novel therapeutic target in human cancer.
PSMA	FOLH1	Prostate specific membrane antigen (PSMA) is a type 2 integral membrane glycoprotein found in prostate tissues and a few other tissues. It is a possible therapeutic target for prostate cancer.
PTEN	18A2, CAPL, FSP1, MTS1, P9KA, PEL98	Phosphatase and tensin homolog. PTEN acts as a tumor suppressor gene, and is mutated in a large number of cancers at high frequency. The PTEN protein is a phosphatase that is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.
PTK6	Brk	A Src-like nonreceptor tyrosine kinase which may function as an intracellular signal transducer in epithelial tissues. PTK6 is a critical mediator of breast cancer cell migration. It is also implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. As a stress-induced kinase, it promotes apoptosis by inhibiting prosurvival signaling.
S100A1	S100-alpha	A Ca2+binding protein of the EF-hand type, involved in the processes including stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule assembly and PKC-mediated phosphorylation. It displays a tissue-specific expression pattern with highest levels in myocardium and is considered to be an important regulator of cardiac contractility. Accordingly, reduced expression or mutations of S100A1 gene have been implicated in cardiomyopathies.
S100A2		A member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100A2 is a homodimer that undergoes a conformational change upon binding of calcium, and the active form functions in regulating cell proliferation and differentiation, gene transcription, and p53-dependent growth arrest and apoptosis. Reduced expression of S100A2 gene has been implicated in certain carcinomas.
S100A6		A member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100A6 functions in stimulation of Ca2+-dependent insulin release, prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of S100A6 gene have been implicated in melanoma.
Src		A tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in Src gene could be involved in the malignant progression of colon cancer.
TGF-beta 1	TGFB	A member of the transforming growth factor beta superfamily of cytokines, synthesized by many cells. TGF-beta 1 is a multifunctional molecule which perform actions in development, as well as in controlling the immune system.
TGF-beta 2		Transforming growth factor-beta 2 (TGF-beta 2) is known to suppress the effects of interleukin dependent T-cell tumors.
TGF-beta 3		Transforming growth factor beta 3 (TGF-beta 3) is thought to be involved in cellular adhesion and extracellular matrix formation during the process of palate development. Defects in TGF-beta 3 causes a deformity known as a cleft palate. It also plays an essential role in controlling the development of lungs in mammals and controls wound healing.
TGFBR1	ALK-5	A serine/threonine protein kinase that forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm.
TIMP-1		A member of the tissue inhibitors of metalloproteinases (TIMP) family. TIMP1 inhibits most MMPs except membrane-type MMP subfamily by forming non-covalent binary complex, but also interacts with the hemopexin-like (PEX) domain of pro MMP-9. It is a multifunctional molecule with FGF-like activity, and participates in tumor metastasis, angiogenesis, inflammatory responses, as well as CNS homeostasis.
TIMP-2		A member of the TIMP family with a unique role of suppressing the proliferation of endothelial cells. TIMP-2 is thus critical to the maintenance of tissue homeostasis and is involved in the regulation of tumor microenvironment
TIMP-3		Metalloproteinase inhibitor 3
TIMP-4		Metalloproteinase inhibitor 4
TMEFF2
TNF-alpha	TNF, TNFA, TNFSF2, DADB-70P7.1, DIF	The prototypic cytokine of the TNF superfamily, produced mainly by macrophages. TNF-alpha is a multifunctional molecule involved in the regulation of a vriaty of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. It is regarded as a molecular insight in cancer treatment.
Urokinase	PLAU	A serine protease involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. PLAU is a potent marker of invasion and metastasis in a variety of human cancers associated with breast, stomach, colon, bladder, ovary, brain and endometrium. A specific polymorphism in PLAU gene is implicated in late-onset Alzheimer disease and also with decreased affinity for fibrin-binding.
VEGF		Vascular endothelial growth factor. The normal function of VEGF is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels to bypass blocked vessels, as well as to increase microvascular permeability. Overexpression can contribute to diseases. Anti-VEGF therapies are important in the treatment of certain cancers and in age-related macular degeneration.