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.

Natural substances that may help down regulate include licorice, shark liver oil, EGCG, curcumin, amygdalin B17, so miso, Salvestrol, genistein, Reishi, pomegranate, anthocyanidin

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.

Substances that may be helpful to down-regulate over expression are rosemary, quercetin, indole 3 carbinol, and isoflavones.

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.

Class III examples that inhibit over-expression include turmeric (curcumin), ginger, and Boswellia, grapeseed OPG, ECGC, quercetin, rosemary, garlic, omega 3, resveratrol, propolis.

Example of a COX-2 inhibitor prescription drug is celecoxib (Celebrex) that selectively inhibits COX-2 (does not aect COX-1), eective if chemosensitivity shows high ecacy (will need to order celecoxib as additional substance since it is not included in the routine testing).

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.

Class III examples that inhibit over-expression of 5-LOX include curcumin and St. John’s Wort. Example of a 5-LOX inhibitor prescription drug is Zileuton, eective if chemosensitivity shows high ecacy.

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.

Natural substances that may help down regulate include Andrographis, curcumin, Boswellia, fish oils, ALA, NrF2, Kaprex, berberine, dim, genistein, ECGC, I3C, melatonin, metformin, quercetin, R-ALA, Reishi and resveratrol. Over-the-counter drugs include aspirin.

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.

Natural substances that may help down regulate include Andrographis complex, curcumin, Boswellia, fish oils, ALA, NrF2, Kaprex, berberine, milk thistle

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..

Treatment for cases with fusion of EML4 to ALK include ALK inhibitors (under Small Molecular Weight molecules) such as Crizotinib, Ceritinib, or Alectinib.

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.

KIT tyrosine kinase inhibitors such as imatinib mesylate (Small Molecular Weight molecule) is an example used to treat metastatic GISTs (gastrointestinal stromal tumors). Function is the growth factor receptor. Related to proliferate growth factor receptors.

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.

Substances that may be helpful to down regulate – EGCG, Lycopene, Metformin, garlic, omegas, ALA, zinc, vitamin D, berberine, exercise.

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.

Substances that may be helpful to down regulate - Metformin, garlic, omegas, ALA, and zinc.

EGF
Epidermal Growth Factor – growth factor proliferation stimuli

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

A common Small Molecular Weight molecule (targeted drug) that inhibits EGFr is Osimertinib (Tagrisso), eective if chemosensitivity shows high ecacy.

Natural substances that can down regulate are berberine, curcumin EGCG, grape seed extract, milk thistle, quercetin, resveratrol, genistein.

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 the growth factor receptor.

Related to HER1. Overexpression of this gene means it is a growth factor support for disease progression.

Natural substances include VascuStatin, C-Statin, Genistein, anthocyanidin, feverfew, artemisinin, bilberry.

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 the growth factor receptor. Related to HER2/neu. HER2/neu encodes for surface cell receptors that signal cell division.

This HER2 receptor is the target for Trastuzumab (Herceptin).

Natural substances that can help down regulate include emodin, quercetin, EPO, monoterpenes, garlic, fish oil, IP6, ALA; low glycemic foods.

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

Involved in autoimmune diseases and malignancies. It is related to the 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, dierentiation, or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. Function is the 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 the 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 the 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 the signal transduction pathway. Related to the transduction pathway.

A common Small Molecular Weight molecule (targeted drug) that inhibits this pathway is Trametinib (Mekinist), which is a MEK inhibitor, and Dabrafenib (Tafinlar), which is a BRAF kinase inhibitor, effective if chemosensitivity shows high efficacy.

Natural substances that may be helpful to down regulate are garlic, omegas, CoQ10, and quercetin, berberine, curcumin. Refer to Class III agents in the Onconomics Extracts (Class III natural substances include inhibition of signal 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 the signal transduction pathway. Related transduction pathway.

A common Small Molecular Weight molecule (targeted drug) that inhibits mTOR is Everolimus/Temsirolimus, effective if chemosensitivity testing shows high efficacy.

Natural substances that may be helpful to down regulate include systemic enzymes, resveratrol, green tea, curcumin, ginseng and metformin. Exercise and fasting have been found to be helpful also.

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.

Examples of Small Molecular Weight molecule (targeted drug) that inhibits or blocks Estrogen include the selective ER modulators (SERMs) Anastrozole,

Exemestane, Tamoxifen, and Fulvestrant. These agents are eective if chemosensitivity shows high ecacy.

Class III examples that inhibit over-expression of Estrogen Receptors include DIM, and Myomin (natural aromatase inhibitor). Indole-3-Carbinol decreases the eects of Estrogen.

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.

Natural substances that may help down regulate include soy, green tea, polyphenol; decrease strenuous exercise & omega 3 oils.

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.

Natural substances that may help down regulate include Pygeum, nettles, pumpkin seeds & oil, green tea, soy isoflavones, beta sitosterol, L-lysine, zinc, vitamin D3, GLA/EPA

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.

Natural substances that help down regulate include vitamin A, genistein, vitamin D3, curcumin, quercetin, melatonin, IP6, resveratrol, PSK, Coriolus versicolor (Turkey Tail)

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, the cell is unable to self-repair. When down-regulated, the 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, the cell is unable to self-repair. Down-regulation means sensitivity to damage by radiotherapy/hyperthermia.

EGCG and Quercetin are synergistic to help regulate this.

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 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.

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

Natural substances that can help down regulate are curcumin, ECGC, Grape Cyanidins, milk thistle, parsley, quercetin, rosemary and sulforaphane.

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.

Curcumin and EGCG can help regulate this hypo methylation.

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.

Natural substance that may be helpful to down regulate is Acetyl-L-Carnitine

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.

Natural substance that may be helpful to down regulate is Acetyl-L-Carnitine

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 drugs. 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. HDAC 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.

Curcumin and ECGC can help with this hypo methylation.

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.

PARP inhibitors are in the SMW molecules class and include Niraparib (Zejula), and Olaparib (Lynparza) routinely in our Onconomics Plus test.

Natural substances that are PARP inhibitors include fermented wheat germ extracts (example Avemar Pulvis and Metoprolol Pro), red wine, coffee, niacin and R-alpha lipoic acid.

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.

Monoclonal antibodies that are often showing high efficacy in chemosensitivity testing include bevacizumab (Avastin) and ramucirumab (Cyramza).

Natural substances include Acetyl-L-Carnitine, VascuStatin, C-Statin, genistein, anthocyanidin, feverfew, artemisinin, bilberry.

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.

Natural substances include VascuStatin, C-Statin, Genistein, anthocyanidin, feverfew, artemisinin, bilberry, bromelain, modified citrus pectin, and Reishi.

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.

Natural substances include VascuStatin, C-Statin, Genistein, anthocyanidin, feverfew, artemisinin, bilberry, EGCG, and Reishi.

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 eects. It enhances stability of newly formed vessels, inhibits vascular permeability induced by several inflammatory cytokines, and attenuates pathological responses, including fibrosis.

Natural substances include gum arabic, lactoferrin.

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.

Natural substances include gum arabic, lactoferrin

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 in the 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).

Substances that may be helpful to down regulate are systemic enzymes, resveratrol, ECGC, curcumin, ginseng, metformin, melatonin, quercetin, modified citrus pectin.

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 with. 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.

Hyperthermia, curcumin, fish oil, selenium, vitamin E (Unique E), CAPE (caffeic acid phenethyl ester) found in propolis, flavonoids (apigenin, luteolin, quercetin, genistein EGCG), IP6 can be natural approaches to help down-regulate.

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.

Substances that may be helpful to down regulate are curcumin, feverfew, Metformin and statins.

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, alkaloid 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.

Natural substances that may be helpful to up regulate are green tea, Genistein and vitamin D3.

P53
Tumor Protein P53 – Cell Cycle Regulation - Apoptosis

TP53 (p53) gene encodes the tumor suppressor protein p53. It is a gene that encodes th 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.

Natural substances that may be helpful to down regulate are melatonin, curcumin, resveratrol, EGCG, garlic, genistein, grapeseed OPCs, milk thistle, quercetin, retinoic acid, selenium trans resveratrol.

P16
Cyclin Dependent Kinase Inhibitor 2A – Cell Cycle Regulation

It is a protein involved in regulation of cell cycle. The 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.

Natural substances that may help to down regulate include Boswellia, garlic, EPA/DHA, flavonoids, hypericin (St. John’s Wort), resveratrol, melatonin, alpha lipoic acid, garlic, curcumin, resveratrol.

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.

The CDK4/6 inhibitor under SMW molecule routinely tested includes Palbociclib (Ibrance). Other CDK4/6 inhibitors not tested routinely include Ribociclib (Kisqali), and Abemaciclib (Verzenio).

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 active 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 reversible, 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 eective 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.

Supplements that may be helpful in decreasing Cyp1B1 include St. John’s wort, Apigenin, Ginseng, Lycopene, Chrysoeriol (in rooibos tea and celery), Naringenin (in grapefruit juice), Zyflamend (a polyherbal formulation from rosemary, turmeric, ginger, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap), and Quercetin.

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 the 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.

Treatment is directed at the aected cell line but will reduce cytokine response, prolonged depletion of T cells, B cells, NK cells, and monocytes. The treatment involves other medications such as filgrastim for neutropenia, epoetin alfa for anemia or transfusion of blood products.

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.

Anti-CD20 antibodies are used for the treatment of B cell tumors such as Burkitt lymphoma, NHL, and CLL. Several monoclonal antibody therapy against CD20 include: Rituxan (rituximab), Zevalin (ibritumomab tiuxetan), Bexxar (tositumomab), Gazyva (Obinutuzumab), and Arzerra (ofatumumab). Function in development and differentiation of B cells into plasma cells. Lymphoma related antigen.

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.

Natural substances that may help down-regulate include curcumin, EGCG, quercetin, fish oils, selenium, modified citrus pectin, resveratrol, melatonin, genistein

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.

3 PD-L1 inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are approved cancer immunotherapies. Oftentimes when PD-1, PD-L1, and PD-L2 are over expressed, the Class II immunomodulator/immunostimulant natural substances Fucoidan, Boswellia Serratta, Alpha Lipoic Acid, and Mistletoe may show as effective agents.

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.

Monoclonal antibody blockade of PD-1 or one of its ligands, PD-L1 removes the suppressive effects of PD-L1 on cytotoxic T cells with restoration of host immunity against the tumor. This treatment can control or eliminate advanced malignant neoplasms, including metastatic melanoma. 2 PD-1 inhibitors approved are pembrolizumab (Keytruda) and nivolumab (Opdivo).

Both are human IgG4 monoclonal antibodies that block PD-1 and are indicated in the treatment of a broad range of tumor types.

Oftentimes when PD-1, PD-L1, and PD-L2 are over expressed, the Class II immunomodulator/immunostimulant natural substances Fucoidan, Boswellia Serratta, Alpha Lipoic Acid, and Mistletoe may show as effective agents.

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.

Oftentimes when PD-1, PD-L1, and PD-L2 are over expressed, the Class II immunomodulator/immunostimulant natural substances Fucoidan, Boswellia Serratta, Alpha Lipoic Acid, and Mistletoe may show as effective agents.