ONCOGENESIS A multistep process comprised of

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1 by Dr JO Serrentino The seminar/webinar is for the purposes of continuing education and available to registrants only. No part of this material may be duplicated in any format without the expressed written permission of the author. No part of this presentation can be used in any form or medium, and is not for unauthorized distribution. The information and suggestions in this document are for informational purposes only; for continuing education registrants only Copyrighted material any duplication or unauthorized use is prohibited JO Serrentino. ONCOGENESIS A multistep process comprised of Initiation Promotion Progression Oncogenesis has layered effect on the CELLS and the immune response or signaling of the cells to alter their function of continuing education series. 1

2 INITIATION An alteration to target cells or tissues caused by exposure to a carcinogen Requires carcinogen to interact with DNA Fixation occurs whereby the alteration is proliferated in at least one generation of cells (one round of proliferation) Altered cells develop focal proliferations that lead to progressive malignancy PROMOTION Overlaps the initiation phase during the fixation of focal proliferation which manifest as lesions when influenced by a promoter Promotion is a long-term process that causes alterations to tissue such as: Inflammation Cellular hyperplasia Differentiation Biochemical changes Only ongoing influence by a promoter on initiated tissue will cause the development of a tumor, thus promotion can be interrupted before a tumor is formed. of continuing education series. 2

3 PROGRESSION Arises as a result of the subtle changes that have occurred during initiation and promotion Cells become more anaplastic showing more malignant behavior some cells turn into latent tumors Importance of micro-environment in this phase When tissue develops malignancy and benign tumors can become malignant NEOPLASIA Neoplasms are classified according to their histogenic origin and the biological behavior of their cells patterns of growth BUT neoplastic cells may not resemble their histogenic origin in morphology, function or in behavior Benign tumors are usually well differentiated FAILURE OR LOSS OF DIFFERENTIATION IS A SIGNATURE FEATURE OF MALIGNANCY BEHAVIOUR of continuing education series. 3

4 THE CELL CYCLE Normal cells divide and differentiate in a 4 phase cell cycle DNA is synthesized during the cell cycle Cell cycle is regulated by cyclins and cyclin kinase complexes Disruption of the cell cycle can lead to tumour formation Cell cycle in neoplastic cells is much longer than in normal cells METASTASIS THE INVASION OF TUMOR CELLS FROM ONE ORGAN TO ANOTHER There are three routes of metastasis: Direct invasion: when portions of the original tumor infiltrate local tissue Implantation: when neoplastic cells spread through the body cavity and implant and proliferate Vascular spread: vascularization through blood vessels and lymphatic tissue of continuing education series. 4

5 TUMOR SUPPRESSOR FACTOR GENES THAT HALT PROLIFERATION OF NEOPLASTIC CELLS Most cancers are caused by the inactivation of tumor suppressor genes Important therapeutic target Halts proliferation of neoplastic cells Slows down proliferation of neoplastic cells P53 A transcription factor that modulates gene expression Induces cell cycle arrest Induces apoptosis thereby preventing tumorigenesis Diffuses oncogenic complexes Antagonist to cell proliferation in the promotion stage Represses differentiation Activated during DNA damage Monitors and enforces tumor suppression Regulates transcription esp. during stress response Regulates autophagy Suppresses exaggerated cell proliferation and behavior during the promotion and progressive stages of cancer Wide application to a variety of cancers in its transcriptional activity of continuing education series. 5

6 ANGEOGENESIS when capillaries from the surrounding tissue vascularize the neoplasm, thereby nourishing neoplastic cells Provides nutrients and oxygen to neoplastic cells Maintains growth and survival The degree of angiogenesis correlates with the rate of growth and the behavior of neoplasms When neoplasms are vascularized, cells are shed into the bloodstream and oncogenesis becomes more aggressive and thus more difficult to control Removal of tumors often causes increased vascularization and metastasis IL-12 A POTENT ANGIOGENIC INHIBITOR Required for endogenous inhibition of angiogenesis Mediates angiostatin s activity Blocks Vascular Endothelial Growth Factor (VEGF) Important in cancer management Adjunct in cancer therapy of continuing education series. 6

7 CYTOKINES TO AVOID AND TO FAVOR Main cytokines expressed in cancer IL-8 is the most common cytokine expressed in tumous and neoplastic cells. IL-8 is angiogenic Others include: TNF IL-6 GROWTH FACTORS ARE CONTRAINDICATED IN CANCER THERAPY OR SUPPORT USEFUL CYTOKINES INCLUDE: IL-12 INF alpha & gamma IL-4 IL-2 IL-10 AIL-1 G-CSF INTERFERON (IFN) IFN alpha is antiproliferative Inhibits tumor angiogenesis Anchors growth and progression Mediator in cell cycle Synergistic with IL-12 of continuing education series. 7

8 IL-4 Can be used in supportive therapy Best combined with oligonucleotides (as in allopathic cancer therapy) Can be anti-inflammatory May be useful as immune booster during chemotherapy May be combined with IFN and Rerio Downregulates IL-8 Vasopermeable IL-2 Used in allopathic cancer therapies with DNA vaccines Used in allopathic medicine to increase absorption of chemotoxin in chemotherapy DO NOT CONFUSE WITH ITS RECEPTOR IL-2R, MORE FREQUENTLY USED IN CANCER THERAPY of continuing education series. 8

9 TUMOR MICRO-ENVIRONMENT Cells of the connective tissue in the vicinity of the tumor can function as promoters Vascularization of tumors is within the microenvironment The tumor microenvironment is a therapeutic target Possible protocol for SUPPORTIVE THERAPY RERIO: A recombinant protein of p53 Anti-oncogenic can be use to prevent tumorigenesis and metastasis. Can be used during or after or in lieu of chemotherapy Compatible with all cancer types Useful for benign tumors to prevent differentiation and progression GENERAL PROTOCOL FOR MALIGNANT TUMOUR: RERIO: 20 DROPS TID FOR 1-2 MONTHS, THEN BID FOR 2 MONTHS, THEN 3 X WEEK FOR 2-4 MONTHS. IL-12: 20 DROPS SID FOR 1-2 MONTHS, THEN 3 X WEEK FOR 1 MONTH GERNERAL PROTOCOL FOR BENIGN TUMOUR: RERIO: 20 DROPS BID FOR 1-2 MONTHS, THEN 3 X WEEK FOR 2-4 MONTHS AIL:1: 20 DROPS BID FOR 1 MONTH, THEN 3 X WEEK FOR 1-2 MONTHS OPTIONAL: BASIC: 1 PACKET FOR 5-10 DAYS IN A ROW, THEN 3 X WEEK FOR 1 MONTH. REPEAT AFTER 10 DAYS. of continuing education series. 9

10 SUPPORTIVE PROTOCOL TO USE WITH CHEMOTHERAPY TO PREVENT MUCOSITIS AND NEUTROPENIA Granulocyte colony stimulating factor (G-CSF) Is commonly used to prevent mucositis in chemotherapy patients. It prevents neutropenia (which often results from chemotherapy) Use post-chemo or during chemo, but always short term. G-CSF: 10 drops sid 10 days in a row, then 3 x week for 1 month. Stop. PREVENTION IN BENIGN TUMOURS RERIO: 20 DROPS BID FOR 1-2 MONTH, THEN 3 X WEEK FOR 2 MONTHS IL-12: 20 DROPS SID FOR 1 MONTH, THEN 3 X WEEK FOR 1 MONTH. AIL-1: 20 DROPS SID FOR 1 MONTH, THEN 3 X WEEK FOR 1-2 MONTHS Using Rerio for its tumour suppression feature and an anti- angiogenesis agent are key components to prevent progression. Rerio here also acts on <cellular stress responsiveness> important in prevention. The anti-angiogenic agent should be A direct blocker of VEGF, so IL-12 is the best choice. AIL-1: inhibits TNF so its added to the micro-environment is useful to protect consequences of tissue damage. Using immune boosters is not recommended in prevention as it could cause progression if not carefully used. of continuing education series. 10

11 GENERAL PREVENTION This is another version of a prevention protocol, which could be given twice a year to prevent cellular senescence in aging people and pets. Vitamin C is an important preventive vitamin to combat pollutants and stress. Guna Basic can be added when there are or have been parasitic infections or candida or fungal infections. RERIO: 20 DROPS SID FOR 1 MONTH, THEN 3 X WEEK FOR 1-2 MONTHS IL-4: 10 DROPS SID FOR 1 MONTH, THEN 3 X WEEK FOR 1 MONTH Take together OPTIONAL: VITAMIN D: iu VITAMIN C: 2-3 g daily GUNA BASIC: 1 packet 5 days in a row, then 3 x week for 2 months. Protocol can be repeated twice a year. GENERAL VETERINARY Dosage chart for systemic therapy (per dose): 10 lbs or less = 1-2 drops lbs = 3-5 drops lbs = 8 drops lbs = 10 drops Giant dogs = 12 drops Horses = 1 ml (35 drops) RERIO: BID FOR 1 MONTH, THEN 3 X WEEK FOR 1-2 MONTHS. Usually repeat IL-4: SID FOR 2 WEEKS, THEN 3 X WEEK FOR 1 MONTH IL-12: SID FOR 1 MONTH, THEN 3 X WEEK FOR 1 MONTH VITAMIN D& C Optional : IFN alpha sid for 2 weeks, then 3 x week for 1 month ( when benign tumors are present or following surgery) of continuing education series. 11

12 REFERENCES Goh A, et.al. Using targeted transgenic reporter mie to study promoter-specific p53 transcriptional activity. Proc natl Acad Sci USA 2012 January 31; 109(5) Junttila MR, et.al. Selective activation o fp53-mediated tumor suppression in high-grade tumour. Nature. 2010; 468: Fedser DM, et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 2010; 468; Kajiwara A, et.al. Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumorspecific Th1-type immune response. Oncol Rep 2012 Ju; 27(6) Zhao X, et.al. Zebrafish p53 protein enhances the translation of its own mrna in response to UV irradiation and CPT treatment. FEBS lett apr.24;586(8) Wen R. et.al. Zebrafish Mms2 promotes K63-linked polyubiquitination and is involved in p53-mediated DNA-damage response. DNA Repair 2012 Feb 1;11(2) Abhinav K, et.al. p53 regulates cell cycle and micrornas to promote differentiation of human embryonic stem cells. PloS Biol February 10(2) Saunthararajah Y. et. al. p53-independent, normal stem cell sparing epigenetic differentiation therapy for myeloid and other malignancies. Semin Oncol 2012 Feb; 39(1) Frazier DP, et.al. Dmp1 physically interacts with p53 and positively regulates p53 s stability, nuclear localization, and function. Cancer Res 2012 apr 1; 72(7) Taira N, Yoshida K. Post-translational modifications of p53 tumor suppressor: determinants of its functional targets. Histol Histopathol 2012 Apr. 27(4) Xu-Monette ZY; Young KH. The TP53 tumor suppressor and autophagy in malignant lymphoma. Autophagy 2012 May 1;8(5) Zhao X, et.al. Recovery of recombinant zebrafish p53 protein from inclusion bodies and its binding activity to p53 mrna in vitro. Protein Expr Purif 2010 aug;72(2) Shang B, et.al. Deciphering the key features of malignant tumor microenvironment for anti-cancer therapy. Cancer Microenviron 2012 May 17 of continuing education series. 12