Growth Factors Proliferation Stimuli (6/19)

P180 - Ribosome-binding protein 1 or RRBP1 

RRBP1 is detected as a ribosome-binding protein located on the rough ER and associated with unfolding protein response. It is upregulated in a wide variety of cancer cells. RRBP1 could alleviate ER stress and help cancer cells survive. Function is pre-protein for cellular stress. Related to tyrosine kinase growth factor.

Bcr-abl (BCR/ABL fusion gene) - A fused protein expressed in hematological malignancies and in GIST

The existence of this chimeric protein reveals an aggressive phenotype. This protein can be a target for drugs like imatinib mesylate (Gleevec). This fusion
protein is considered a primary oncogenic driver of chronic myelogenous leukemia (CML). If expressed, it is diagnostic for CML. Function is fusion protein. Related to resistant phenotype.

PTEN - Phosphatase and Tensin Homolog – Proliferation

PTEN is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers. PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle,
preventing cells from growing and dividing too rapidly. PTEN is a repair related gene. PTEN dysfunction causes dysregulation of the PI3K/AKT/mTOR growth-promoting signaling cascade, resulting in overgrowth. Function is to repair related genes. Related to tumor suppressor genes.

COX2 - Prostaglandin-Endoperoxide Synthase 2 (PTGS2) – Tumor Growth

This is an enzyme responsible for inflammation and pain. It is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase involved in the metabolism of eicosanoids and indirectly promotes carcinogenesis and metastasis process in cancer cells. Function is eicosanoid related protein. Related to tumor growth.

5-LOX - Arachidonate 5-lipoxygenase (ALOX5) – Tumor Growth

This is an enzyme responsible for producing inflammatory leukotrienes. It is involved in the metabolism of eicosanoids and indirectly promotes
carcinogenesis and metastasis process in cancer cells. Function is eicosanoid related protein. Related to tumor growth.

NFkB - Nuclear Factor Kappa B Subunit Family – Immune Response – Cell Cycle Regulation

Regulates the proteasome activity for degradation of intracellular proteins and at the same time regulates transcription of multiple genes that regulate cell cycle. Function is proteasome inhibitors. Related to transcription factor.

lkB (a,b,c) - Component of Inhibitor of Nuclear Factor Kappa B Kinase Complex – Immune Response – Cell Cycle Regulation

Regulates the proteasome activity for degradation of intracellular proteins and at the same time regulates the transcription of multiple genes that
regulate cell cycle. Function is proteasome inhibitors. Related to inhibitors of NFkB.

ALK - Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK). Involved in growth factor proliferation stimuli

“Anaplastic lymphoma kinase also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene. ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.” ALK is associated with cancer formation of different types such as lung cancer, breast cancer, anaplastic large cell lymphoma, and neuroblastoma by
abnormal fusion or non-fusion of activated ALK. Function is proto-oncogene. Related to acute leukemia kinase.

EML-4-ALK - Proliferation

It is a characteristic abnormal configuration of DNA wherein the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the ALK gene.
This abnormal fusion leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of
the cancer cells. Function is proto-oncogene. Related to fusion EML with ALK..

NPM-ALK - Proliferation

NPM-ALK’s transcription is under the control of NPM regulatory sites. NPM is a ubiquitously expressed protein that is predominantly found in the nucleolus but can shuttle between the cytoplasm and nucleus. NPM is multifunctional and regulates several cellular activities including transcription, ribosome biogenesis, and the shuttling of proteins between the nucleus and cytoplasm. The NPM-ALK fusion gene consists of the first four exons of NPM which encodes for the first 117 amino acids of the NPM protein, and the ALK portion of the fusion includes the exons encoding for the intracellular tail and kinase domain of ALK. NPM-ALK positive lymphoma cells highly express immunosuppressive cell-surface receptor PD-L1, physiologically expressed by
immune cells and binds to PD1 on the surface of CD4+ and CD8+ lymphocytes. It enhances the induction of T-cell tolerance to self-antigens during an immune response, ultimately leading to immune evasion (immune escape). Function is proto-oncogene. Related to fusion NPM with ALK.

RET - Ret Proto-Oncogene – Proliferation

The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line derived neurotrophic factor family of extracellular signaling
molecules. RET loss of function mutation is associated with the development of Hirschsprung's disease, while gain of function mutations are associated
with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasia type 2A and 2B, pheochromocytoma and parathyroid hyperplasia. Function is proto-oncogene. Related to proto-oncogene.

Growth Factors Proliferation Stimuli (7/11)

SS-r - Somatostatin Receptor 1 (SSTR1) – Growth Factor Proliferation Stimuli

Somatostatin Receptor with stimulatory effect in neuroendocrine cancers. Neuroendocrine tumors (NETs) frequently exhibit high expression levels of
SSTRs (SSTR1 is one of the 5 subtypes). Function is a growth factor. Related to somatostatin receptors.

CD117 (c-kit) - KIT Proto-Oncogene, Receptor Tyrosine Kinase (KIT) – Growth Factor Proliferation stimuli

Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and
proliferation, haematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration, and function, and in melanogenesis. It is a type
III receptor tyrosine kinase that works in the cell signal transduction pathway. Clinical relevance is seen in KIT positive cells as in sarcomas, lung small cell
carcinomas, renal chromophobe carcinoma, some ovarian and some breast carcinomas.

IGF-r 1 - Insulin Like Growth Factor 1 Receptor – Growth factor proliferation stimuli

It is a growth factor receptor that activates the intracellular mitotic mechanism. Increased IGF levels are inversely associated with longevity and
positively associated with cancer risk. Overexpression promotes mitosis, metastasis, and drug resistance. Function is the growth factor receptor. Related to insulin like growth factor receptors.

IGF-r 2 - Insulin Like Growth Factor 2 Receptor – Growth factor proliferation stimuli

It is a growth factor receptor that activates the intracellular mitotic mechanism. Increased IGF levels are inversely associated with longevity and
positively associated with cancer risk. Overexpression promotes mitosis, metastasis, drug resistance and is associated with poor prognosis. Function is growth factor receptor. Related to insulin like growth factor receptors.

EGF - Epidermal Growth Factor – growth factor proliferation stimuli

Acts as a potent mitogenic factor that plays an important role in the growth, proliferation and differentiation of numerous cell types. Function is growth factor receptor. Related to tumor growth. Class III natural substances include inhibition of EGFr.

C-erb- B1 - Epidermal Growth Factor Receptor (EGFr)

Receptor tyrosine kinase binding ligands of the EGF family. It activates several signaling cascades to convert cues into appropriate cellular
responses. It encodes growth factor receptors and can become a target for monoclonal antibody therapy – for example, this is a target to Erbitux (Cetuximab). Erbitux is a EGFr inhibitor – binds to the receptor on both normal and tumor cells, results in inhibition of cell growth, and induction of apoptosis. Function is growth factor receptor. Related to HER1.

C-erb B2 (Erb-B2 Receptor Tyrosine Kinase 2 or ERBB2)

Growth factor proliferation stimuli. Human epidermal growth factor receptor 2 (HER2/neu) or Erb-B2 receptor tyrosine kinase 2. Overexpression of this
gene means it is HER2 positive (HER2/neu+). This gene is overexpressed in up to 30 percent of human breast cancers. Function is growth factor receptor.
Related to HER2/neu. HER2/neu encodes for surface cell receptors that signal cell division.

JAK 1 and JAK 2 - Janus Kinase Family – Growth factor proliferation stimuli – Cell Signaling

Involved in autoimmune diseases and malignancies. It is related to signal transduction pathway. 

JAK1 is essential for IL-6 class inflammatory cytokine signaling.

JAK2 is important for control of blood cell production from hematopoietic stem cells.

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation, or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. Function is signal transduction pathway. Related to signal transduction pathway.

c-Jun - Jun Proto-Oncogene (JUN) – Proto-Oncogene

FOS and JUN are the final monomers of transcription factors AP-1 which promotes cancer cell proliferation. The function is signal transduction pathway. Related to proto-oncogene.

c-Fos - Fos Proto-Oncogene, AP-1 Transcription Factor Subunit (FOS) – Proto-Oncogene

Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. FOS and JUN are the final
monomers of transcription factors AP-1 which promotes cancer cell proliferation. The function is signal transduction pathway. Related to proto-oncogene.

Ras-Raf-MEK-Erk - MAP Kinase Pathway – cell signaling.

Signal transduction pathway that stimulates cancer cell proliferation. Overexpression of this gene signals cancer cells to increase proliferation or to
continuously promote proliferation. Function is signal transduction pathway. Related to transduction pathway.

MTor - Mechanistic Target of Rapamycin Kinase – cell signaling

Signal transduction pathway that stimulates cancer cell proliferation. Overexpression of this gene signals cancer cells to increase proliferation. Function is signal transduction pathway. Related transduction pathway.

Progesterone Receptor - Progesterone Receptor (PGR) – Growth Factor Proliferation Stimuli

Receptors are stimulated from the relevant ligands and drive the female to genital cancers. PR is an upregulated target gene of ER. PR can modulate ER action. In clinical practice, there is a higher response to Selective Estrogen Receptor Modulators (SERMs) in PR positive breast cancer than in PR negative breast cancer. If positive (over expressed) then consider hormone suppression (even if tumor biopsy was negative). Function is hormone receptors. Related to growth factor receptors.

Estrogen-Receptor - Estrogen Receptor 1 (ESR1) – Estrogen Receptor 2 (ESR2)

Receptors are stimulated from the relevant ligands and drive the female to genital cancers. If positive, then consider hormone suppression (even if
tumor biopsy was negative). Almost 70 percent of breast cancers are hormone receptor positive.

NR3C4-A - Androgen Receptor (AR) – Growth Factor

Nuclear receptor of androgen (Testosterone), which promotes the male genital cancer. If positive, consider hormone suppression (even if tumor
biopsy was negative). Function is hormone receptors. Related to growth factor receptors.

NR3C4-B - Androgen Receptor (AR) – Growth Factor

Nuclear receptor of androgen (DHT), which also promotes male genital cancer. If positive, consider hormone suppression (even if tumor biopsy was
negative). Function is hormone receptors. Related to growth factor receptors.

Self-Repair – Resistance (8/19)

TGF-b - Transforming Growth Factor Beta (TGF-b) – Self-Repair – Resistance

It is a protein that controls proliferation, cell differentiation and other functions in most cells. It is a type of cytokine which plays a role in immunity, cancer, diabetes, etc. It’s under the function of signal transduction, related to tumor growth when dysregulated.

HSP27 - Heat Shock Protein Family B (Small) Member 1 – Self Repair – Resistance

Family of proteins that promote cell self-repair after cell damage due to radiation or hyperthermia. When down-regulated, cell is unable to self-repair. Down-regulation means sensitivity to damage by radiotherapy/hyperthermia.

HSP72 - Heat Shock Protein Family A (Hsp70) Member 1A – Self Repair – Resistance

Family of proteins that promote cell self-repair after cell damage due to radiation or hyperthermia. When down-regulated, cell is unable to self-repair. When down-regulated, cell is unable to self-repair. Down-regulation means sensitivity to damage by radiotherapy/hyperthermia.

HSP90 - Heat Shock Protein 90 Alpha Family Class A Member 1 – Self-Repair – Resistance

Family of proteins that promote cell self-repair after cell damage due to radiation or hyperthermia. When down-regulated, cell is unable to self-repair. Down-regulation means sensitivity to damage by radiotherapy/hyperthermia.

DNA methyltransferase I

It is involved with DNA super coiling and uncoiling mechanisms through methylation and alkylation of DNA in specific base-pair CpG. This is the way
DNA locks and unlock genes and by this method they escape the activity of the gene blockers. Function is under resistant phenotype markers. Related to DNA methylation.

DNA-demethylase - KDM Family – Self-Repair – Resistance

It is involved with DNA super coiling and uncoiling mechanisms through methylation and alkylation of DNA in specific base-pair CpG. This is the way
DNA locks and unlock genes and by this method they escape the activity of the gene blockers. Function is resistant phenotype markers. Related to DNA methylation.

06-methyl-DNA-tran - O-6-Methylguanine-DNA Methyltransferase (MGMT) – Self-Repair – Resistance

It is involved with DNA super coiling and uncoiling mechanisms through methylation and alkylation of DNA in specific base-pair CpG. This is the way
DNA lock and unlock genes and by this method they escape the activity of the gene blockers. Function is resistant phenotype markers. Related to DNA methylation.

Histone-deacetylase-dipeptide

Related to DNA coiling (nucleosome). Function is under resistant phenotype markers. The enzymes allow histones to wrap the DNA more tightly.

HAT - Histone Acetyltransferase Family – Self Repair-Resistance

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression. The chromatin opens and allows gene transcription. Histone acetylation is linked to
transcriptional activation and associated with euchromatin. When it was first discovered, it was thought that acetylation of lysine neutralizes the positive
charge normally present, thus reducing affinity between histone and (negatively charged) DNA, which renders DNA more accessible to transcription factors. Histone acetyltransferases can also acetylate non-histone proteins, such as transcription factors and nuclear receptors to facilitate gene expression.

CXCR4 - C-X-C Chemokine Receptor 4 (CXCR4) – Self Repair-Resistance

Receptor for the C-X-C chemokine CXCL12 ligand. Implicated in tumor invasion, metastasis, and immune cell trafficking. Important role to cell repair
and resistance of cancer cells to alkylating agents. High expression is associated with poor prognosis in colorectal cancer. High expression is also
associated with improved outcome after checkpoint inhibition immunotherapy in colorectal cancer.

CXCL12 - C-X-C Chemokine Ligand 12 (CXCL12) – Self Repair-Resistance

Also known as SDF-1 or stromal-derived-factor-1. It is the ligand for the G-protein coupled receptor, chemokine (CXCR4), and plays a role in many
diverse cellular functions, including embryogenesis, immune surveillance, inflammation response, tissue homeostasis, and tumor growth and
metastasis. Important role to cell repair and resistance of cancer cells to alkylating agents. Interaction of CXCL12 and CXCR4 causes tumor cells to form metastatic tumors.

Gamma GC - Gamma-Glutamyl Carboxylase (GGCX)

This gene is involved in the glutathione pathway, which is important to xenobiotics. It inactivates many foreign substances including cytostatic drug. Function is under resistant phenotype markers. Related to resistance to alkylating drugs. If dysregulated, the inactivation of substances is affected.

HDAC - Histone Deacetylase Family – Self Repair-Resistance

Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing
the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and deacetylation. Its action is opposite to that of histone acetyltransferase. HDACs have a repressive effect on gene expression. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. Deregulation is involved in hematological malignancies. The HDAC family members are attractive drug targets. Key issues are limited efficacy and drug resistance.

PARP (1-17) - Poly (ADP-Ribose) polymerase (PARP)

This is a family of proteins involved in DNA repair, genomic stability, and programmed cell death. There are 17 members in this PARP family. PARP is
found in the nucleus of a cell. Its main role is to detect and initiate immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks by signaling the enzymatic machinery involved in the SSB repair. PARP functions as a DNA repair related gene. Mutated cancer cells use this enzyme to repair DNA damage from chemo and radiation. Other cellular functions involved include expression of inflammatory genes.

Angiogenesis – Metastases (9/19)

VEGF - Vascular Endothelial Growth Factor A (VEGFA) – Angiogenesis-Metastases

It is a signal protein produced by many cells that stimulate formation of blood vessels. Involves angiogenesis of primary tumor so that it can metastasize to distant organs. It regulates proliferation, migration, and division of endothelial cells. Overexpression in cancer cells helps them grow and metastasize. In vitro, VEGFA has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGFA is also a vasodilator and increases microvascular permeability. Numerous studies show a decrease in overall survival and disease-free survival in those tumors overexpressing VEGF. The VEGF signaling pathway is recognized as the master regulator of developmental and pathological angiogenesis.

FGF - Fibroblast Growth Factor Family

Involves angiogenesis of primary tumor so that it can metastasize to distant organs. It regulates proliferation, migration, and division of endothelial cells. FGF can act synergistically with VEGF to amplify tumor angiogenesis.

PDGF - Platelet Derived Growth Factor Subunit A/B – Angiogenesis-Metastases

Involves angiogenesis of primary tumor so that it can metastasize to distant organs. It regulates proliferation, migration, and division of endothelial cells.

ANG 1 - Angiopoietin 1(ANGPT1) – Angiogenesis

A secreted glycoprotein that belongs to the angiopoietin family and plays important roles in vascular development and angiogenesis. It has been shown
to act as an angiogenic promoter in embryonic angiogenesis by promoting vascular branching, pericyte recruitment and endothelial survival. ANG1 has vascular protective effects. It enhances stability of newly formed vessels, inhibits vascular permeability induced by several inflammatory cytokines, and attenuates pathological responses, including fibrosis.

ANG2 - Angiopoietin 2 (ANGPT2) – Angiogenesis

It is an antagonist of angiopoietin 1 (ANGPT1) and endothelial TEK tyrosine kinase (TIE-2, TEK). The encoded protein disrupts the vascular remodeling
ability of ANGPT1 and may induce endothelial cell apoptosis. During inflammation, ANG2 functions as an antagonist and promotes endothelial permeability in synergy with inflammatory cytokines.

c-MET

c-MET is a tyrosine kinase receptor that, after binding with its ligand, hepatocyte growth factor (HGF), activates a wide range of different cellular
signaling pathways including those involved in proliferation, motility, migration, and invasion. High levels of c-MET and/or HGF expression have been associated with poor patient outcome. Nearly half of lung adenocarcinomas demonstrate high expression of c-MET and HGF. Such high expression patterns have been reported to correlate with increased tumor growth rate and metastasis, poor prognosis, and resistance to radiotherapy.

High levels of c-MET/HGF in breast carcinoma have been correlated with histological grade, poor prognosis, and high proliferative cell index, and even with a greater incidence of metastases. In these reports, c- MET overexpression was observed in hypoxic areas and correlated directly with poorer overall survival. Because of its pleiotropic role in cellular processes important in oncogenesis and cancer progression, c-MET is considered to be an important target in anticancer therapy. In another report, c-MET overexpression might play an important role in acquired resistance to cytotoxic anticancer drugs. When overexpression is seen in RGCC testing, it means the CTCs are actively trying to metastasize.

67LR - 67 kDa Laminin Receptor (RPSA) – Angiogenesis-Metastases

The 67 kDa laminin receptor (67LR) is a non-integrin cell-surface receptor for the extracellular matrix derived from the dimerization of a 37 kDa cytosolic
precursor (37LRP). 67LR is highly expressed in human cancers and widely recognized as a molecular marker of metastatic aggressiveness. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential in solid tumors. 67LR down regulation reduces tumor cell proliferation and tumor formation by inducing apoptosis.

KISS-1 4 - KISS1 Receptor – Angiogenesis-Metastases

The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor which binds the peptide hormone
kisspeptin. Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of
the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell. It is important to
note that KISS1 exhibits dual roles in cancer. KISS1 acts as a suppressor of tumorigenesis and metastasis in many cancers, while in breast and liver cancer it functions as a promoter. But in general, over expression results in a lower metastatic risk and down regulation results in a higher metastatic risk.

Nm23 - NME/NM23 Nucleoside Diphosphate Kinase – Angiogenesis-Metastases

Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene. Also known as non-metastatic protein 23 H1 (Nm23-H1) or non-metastatic clone 23 (Nm23). This gene is a metastatic suppressor (metastasis suppressor protein) identified in melanoma cell line and expressed in different tumors where their levels of expression are associated with reduced or increased metastatic potential. Tumors with alteration of the P53 gene and reduced expression of the Nm23 gene are more prone to metastasis. Nm23 suppresses mets by inhibiting multiple metastatic steps, including invasion of the primary site and colonization. Over expression results in lower metastatic risk and down regulation results in higher metastatic risk.

MMP - Matrix Metallopeptidase Family – Angiogenesis-Metastases

These proteins (metalloproteinases) are involved to infiltration procedure of tumor to surrounding tissues. If serum detection is achievable most MMPs (especially MMP11 and MMP13) have consistently increased gene expression across cancers, while several MMPs have consistently decreased expression in several cancer types (highly pronounced in lung squamous and adenocarcinoma subtypes). Many MMPs have diagnostic value individually or in combination, while the prognostic value of MMPs is restricted to one subtype of kidney cancer (clear cell renal carcinoma).

Cell Cycle Regulation & Immortalization/Apoptosis (10/19)

E2F1 - E2F Transcription Factor 1 – Cell Cycle Regulation

It is a regulatory factor that regulates the expression of multiple proto-oncogenes, it regulates the protein synthesis inside the cell and of course the expression of topoisomerase I and thymidylate synthase (TS).

CDC6 - Cell Division Cycle 6 (CDC6) - Cell Cycle Regulation 

Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.

H-TERT - Telomerase Reverse Transcriptase (H-TERT)

It is the gene for the human telomerase. This regulates the cell time life and the number of cell divisions that a normal cell will proceed. In cancer cells if this gene is overexpressed then the cell becomes immortal with a very aggressive phenotype, and those cells overcome the M2 crisis. M2 crisis is when telomeres become critically short. In most somatic cells, the inactivated telomerase leads telomeres to shorten with each round of cell division, and the cells lose the capacity to replicate when a critical length has been reached. Activated telomerase-induced cancer cells escape from telomere shortening and ultimately promote unlimited cancer cell proliferation immortalization. Overexpression of H-TERT was associated with poor survival in human solid tumors.

Bcl-2 - B-cell lymphoma 2 - Apoptosis Regulator – Apoptosis (cell-death)

It is an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells. Regulates cell death by controlling the mitochondrial membrane permeability (either by inhibiting or inducing apoptosis). In follicular lymphoma, a chromosomal translocation commonly occurs between the 14th and 18th chromosome, which places the Bcl-2 gene from chromosome 18 next to the immunoglobulin heavy chain on chromosome 14. This fusion gene is deregulated leading to high levels of Bcl-2. High levels of Bcl-2 decreases propensity of these cells for apoptosis.

Bax - BCL2 Associated X, Apoptosis Regulator (BAX) – Apoptosis

It belongs to the BCL2 protein family. Forms a heterodimer with BCL2, and functions as an apoptotic activator.

CD95 (fas-r) - Fas Cell Surface Death Receptor (FAS) – Apoptosis

It is the extrinsic receptor for inducing apoptosis. Plays a central role in the physiological regulation of programmed cell death and has been implicated in the pathogenesis of various malignancies and diseases of the immune system.

P27 - Cyclin Dependent Kinase Inhibitor 1B – Cell Cycle Regulation. P27 (Kip1) protein (encoded by CDKN1B)

Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. P27 binds and inhibits cyclin-CDK to arrest the cell cycle. It freezes the cell cycle and by this way makes the cell overpass the activity of cell cycle dependent cytostatics (taxanes, alkaloids of vinca, purine and pyrimidine analogue, topoisomerase I and II inhibitors). In other words, cancer cells with high overexpression of P27 do not respond as well with cell cycle dependent chemo agents.

P53 - Tumor Protein P53 – Cell Cycle Regulation - Apoptosis

TP53 (p53) gene encodes the tumor suppressor protein p53. It is a gene that encodes the very famous p53 which is a switch-control point of cell cycle. It regulates when a cell will go to apoptosis after cell damaging or it will proceed to self-repair. Non regulation to this point usually leads to carcinogenesis. P53 gene is mutated or deleted in approximately half of all cancers, and the P53 signaling pathway is disrupted in the remaining half. Dysfunction of P53 gene is a hallmark of many human malignancies.

P16 - Cyclin Dependent Kinase Inhibitor 2A – Cell Cycle Regulation

It is a protein involved in regulation of cell cycle. CDKN2A gene is also known as P16 gene. It encodes multiple tumor suppressor 1 (MTS1), which belongs to the INK4 family. This protein can bind to CDK4 and CDK6 and inhibit the formation of kinase activity complexes by cyclin D (CD) and CDK4. The kinase activity complex can prevent RB protein phosphorylation. Cells are stopped in the G phase. Mutation of P16 will remove inhibition of the CyclinD-CDK4 complex. Then, RB protein phosphorylation results in abnormal cell cycle progression, and cells gain unlimited proliferation ability.

P16 is a gene that encodes a protein that regulates the cell cycle. Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor.

CDK4/6

Cyclin-dependent kinase 4 (CDK4) and CDK6 function as cell cycle regulators and are critical mediators of cellular transition into S phase and are important for the initiation, growth, and survival of many cancer types. CDK4/6 inhibitors are the new standard of care for patients with advanced hormone receptor-positive/HER2- breast cancer. CDK4/6 inhibitors arrest sensitive tumor cells in the G1 phase of the cell cycle. The CDK4/6 are frequently dysregulated in malignancies. Overexpression of CDK4/6 leads to cancer cell proliferation.

Drug Metabolism & Targets (11/19)

DPD - Dihydropyrimidine Dehydrogenase (DPYD) – Metabolism It encodes an enzyme that participates in nucleotide (base of DNA and RNA) metabolisms.

If it is not expressed normally then the purine analogue drugs are transformed to acute form, but they cannot remove or transform to non-active forms that can be removed by the urinary tract. This means the drugs have additional activity and toxicities are very high (inherent in 5-FU toxicities). Overexpression of DPD in hepatocellular carcinoma can promote in vitro migration and invasion. Also, high DPD over expression was positively correlated with aggressive tumor behaviors (increasing size, disease recurrence, and advanced stage tumor node metastasis. It is also correlated to poor overall survival following a curative resection.

UP - Uridine phosphorylase 1 (UPP1)

This is a dimeric enzyme that plays a role in pyrimidine salvage, uridine homeostasis and is upregulated in various cancers, including lung adenocarcinoma. It is reported as an oncogene in several malignancies. Studies show that high levels of UPP1 in tumors was usually accompanied with poorer prognosis and shorter survival. Function is in nucleoside import transformation. It is related to resistance to 5FU.

NP - Purine Nucleoside Phosphorylase – Metabolism

This enzyme is involved in purine metabolism, pyrimidine metabolism, and nicotinate and nicotinamide metabolism. It is one of the enzymes of the “nucleotide salvage” pathways when the de novo synthesis pathway has been interrupted as a result of chemotherapeutic drugs such as methotrexate (MTX) or aminopterin. NP is a family of genes that encodes transmembrane proteins that work as ports for nucleotides to transport them to the
intracellular area.

TP - Thymidine Phosphorylase (TYMP) – Metabolism

TP is a nucleoside metabolic enzyme that plays an important role in the pyrimidine pathway. The main metabolic function is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF or PDGF). TP is overexpressed in several cancers in response to cellular stress conditions such as hypoxia, acidosis, chemotherapy, and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of immune-response and resistance to apoptosis. TP also plays a role in cancer treatment through its role in the conversion of oral fluoropyrimidine capecitabine into its active form 5FU.

"It (TP) encodes an enzyme that participates in nucleotide (base of DNA and RNA) metabolism. If it is not expressed normally then the purine analogue drug is transformed to active form, but they cannot remove or transform to non-active forms so that they can be removed by the urinary tract. This means that those drugs have additional activity and toxicities are very high (inheriting 5-FU toxicities)."

TS - Thymidylate Synthetase (TYMS) – Metabolism 

This enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage. This enzyme is involved in the tetrahydrofolate pathway which is the only way for thymidine production for cells. The sensitivity of TS to succumb to TS inhibitors is a key part of its success as treatment for colorectal, pancreatic, ovarian, gastric, and breast cancers. TS can be blocked by 5FU (the most widely used TS inhibitor), FUDR, capecitabine etc. 5FU and its metabolized form 5-FdUMP acts as antimetabolite that irreversibly inhibits TS by competitive binding.

However due to the low level of 5FU in many patients, it was discovered that in combination with leucovorin (LV), 5FU has greater success in down regulating tumor progression mechanisms and increasing immune system activity.

DHFR - Dihydrofolate Reductase – Metabolism

It is involved in the tetrahydrofolate pathway which is the only way for thymidine production for cells. Since folate is needed by rapidly dividing cells to make thymine, the antifolate effect of a DHFR inhibitor is used for therapeutic advantage. DHFR can be blocked by MTX (methotrexate), which prevents neoplastic cells from dividing.

SHMT - Serine Hydroxymethyltransferase 1 (SHMT1) – Metabolism

SHMT is a pyridoxal phosphate dependent enzyme which plays an important role in cellular one-caron pathways by catalyzing the reversile, simultaneous conversions of L-serine to glycine and tetrahydrofolate to 5,10-Methylenetetrahydrofolate. This reaction provides the largest part of the one-carbon units available to the cell. SHMT is involved in the tetrahydrofolate pathway which is the only way for thymidine production for cells. Pemetrexed used as an antifolate to treat mesothelioma was found to be an effective SHMT inhibitor.

GARFT - Phosphoribosylglycinamide Formyltransferase (GARFT)

It is involved in the tetrahydrofolate pathway which is the only way for thymidine production for cells. GARFT can be blocked by pemetrexed, gemcitabine etc. GARFT is an essential step in the synthesis of purine nucleotides, and a target for blocking the proliferation of malignant cells.

Ribonucleotide reductase - Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) – DNA synthesis

Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. It is related to Gemcitabine resistance.

CES1-2 

Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and 6-monoacetylmorphine. Hydrolyzes aspirin, substrates with large alcohol group and small acyl group and endogenous lipids such as triacylglycerol. Function involves activation of Camptothecin. Related to resistance to Camptothecin

CypB1 - Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) – Metabolism

These are the enzymes that eliminate most of the drugs and toxins from the body. This enzyme can activate a wide range of cancer-causing compounds. Increased CypB1 activity was shown to promote the growth and metastases of NSCLC.

It is a protein that involves xenobiotics (exogenous chemicals) and the inactivation of many cytostatic drugs. Xenobiotic metabolism is generally achieved by phase I and phase II enzymes. It is highly expressed in estrogen-mediated cancer.

RRM1

Ribonucleoside-diphosphate reductase large subunit is an enzyme in humans encoded by the RRM1 gene. This enzyme is essential for the production of deoxyribonucleotides prior to DNA synthesis in S phase of dividing cells. It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, lung, ovarian, and breast carcinoma.

Markers (12/19)

CD33
This marker is a member of the sialic acid-binding Ig-like lectins (siglecs), which generally mediate cell-cell interactions and cell signaling. It is
expressed by myeloid stem cells, myeloblasts and monoblasts, monocytes/macrophages, granulocyte precursors (decreasing expression with maturation), and mast cells. It is an excellent myeloid marker and is commonly used for the diagnosis of AML (present as a cell surface antigen in more than 80% of patients with AML). 10-20% of B-lymphoblastic or T-lymphoblastic leukemia/lymphomas may aberrantly express CD33. Function in immune system regulation. Related to myeloid cell origin.

CD52
This protein marker is present on the cell surface of most lymphoid cells and many other hematopoietic cells but not on stem cells. Mature T cell and B cell lymphomas express this antigen (95% of peripheral T and B cells). This antigen is a target for monoclonal antibody therapy Campath 1-H (Alemtuzumab) which is anti-CD52. Function in immune system regulation. It is related to Leukemia marker.

CD20
This is an antigen marker on the surface of B cells but not T cells. Diffuse large B cell lymphoma (DLBCL) involves B cells.

EpCAM
Epithelial cell adhesion molecule is a transmembrane glycoprotein mediating Ca2+ independent homotypic cell-cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies. Function in cell-cell adhesion. Related to epithelial markers.

PD-L1
Programmed-Death Ligand-1 or PD-L1 (CD274), the main PD-1 ligand, is a transmembrane protein expressed on a variety of cell types, including antigen presenting cells (APCs), mainly dendritic cells (DCs) and macrophages and expressed by non-lymphoid tissues including heart, lung, and others. The binding of PD-L1 inhibits the function of activated T-cells, which is an important mechanism for negative feedback control of inflammation and autoimmunity in peripheral effector phase of T-cell activation and identifies the PD-1/PD-L1 pathway as a significant immune response checkpoint. Tumor cells may express PD-L1, with subsequent PD-1 binding and inhibition of T-cell activation allowing cancer cells to evade immune attack.

PD-1
PD-1 (CD279) is a cell surface receptor that is part of the immunoglobulin superfamily expressed primarily on the surface of activated T-cells. Programmed-Death 1 is a key immune checkpoint inhibitory receptor, which is expressed on activated tumor-specific CD4+ helper and CD8+ killer T lymphocytes.

PD-L2
Programmed-Death ligand-2 or PD-L2 (CD273), another ligand of PD-1, is a type 1 transmembrane protein that contains an immunoglobulin (Ig)-like V-type domain and an Ig-like C-type domain in the extracellular region. It is not only expressed in tumor cells but also in immune cells, and its high expression has been proven to play an important role in tumorigenesis and immune escape. Although PD-L2 is structurally similar to PD-L1, the binding affinity between PD-L2 and PD-1 is two to sixfold higher than that with PD-L1, suggesting PD-L2 is an important molecule in immune escape as strong interaction inhibits cytokines secretion and proliferation of T cells.