Simplified description of pathogenesis of cancer

Djo Hasan, MD, PhD, 7th version, 2014‐09‐18 Simplified description of pathogenesis of cancer 1.
Tumour cells are generated during chronic inflammation. This can be induced by intracellular micro‐organisms, repetitive DNA damaging agents (sun rays, X‐rays, chemical compounds), etc. There is a high concentration of free radicals in the chronically inflamed environment. These free radicals are produced by the leukocytes in their action of killing the infected or damaged cells. The toxic environment considerably increases the risk of point mutation, deletions or rearrangements of DNA. 2.
T cell‐mediated immunity against tumour cells includes multiple sequential steps involving the clonal selection of antigen‐specific cells: the activation and proliferation in secondary lymphoid tissues, the trafficking to sites of antigen and inflammation, the execution of direct effector functions and the provision of help (through cytokines and membrane ligands) for a multitude of effector immune cells. Each of these steps is regulated by counterbalancing stimulatory and inhibitory signals that fine‐tune the response. The huge number of genetic and epigenetic changes that are inherent to most cancer cells provide plenty of tumour‐associated antigens that the host immune system can recognize, thereby requiring tumours to develop specific immune resistance mechanisms. Important immune resistance mechanisms involve, among others, immunosuppressive myeloid derived suppressor cells (MDSCs) and immune‐inhibitory pathways, termed immune checkpoints, which normally (in inflammatory processes other than tumour environment) mediate immune tolerance and mitigate collateral tissue damage. 3.
Tumour mass consists of tumour stem cells (20%), more differentiated tumour cells resemble the original tissue which was under repair during chronic inflammation, and the so called tumour matrix. The tumour matrix includes, among others, immunosuppressive T lymphocytes (Tregs), MDSCs, cancer associated fibroblasts (CAFs), and tumour associated macrophages (TAMs). The tumour matrix is in fact an important defence mechanism. Obviously, single tumour cells are more vulnerable to immune attacks than large tumour masses. 4.
Tumour cells can only survive the immunological surveillance when it is protected by an immunosuppressive action of the immune system itself. Immunosuppression is a component of chronic inflammation in attempt to rebuild the damaged tissue in an inflamed environment. Tregs (controlled by the immune checkpoints) and MDSCs act as immunosuppressors and are capable to de‐activate and destroy natural killer cells (NK). 5.
Cancer cells have the following capabilities independent of proliferation signals: a. Evasion of apoptosis, b. Insensitivity to anti‐growth signals, c. Unlimited replicative potential, d. The ability to invade and metastasize and to attract and sustain angiogenesis for nutrient supply. e. Acquisition of multiple drug resistance (MDR) and avoidance of oncogene induced senescence (= biological ageing). 6.
Mutations in patients with tumours lead to loss of natural tumour suppressor proteins (tumour suppressor p53, tumour suppressor phosphatase and tensin homolog PTEN, etc) and the activation of oncoproteins (such as PI3K). 7.
Tumour metabolism is designed to survive hypoxic circumstances during tumour growth. At the same time tumour cells prefer the anaerobic metabolism and produce a high amount of lactic acid that leads to a low pH in the tumour surroundings. a. Tumours utilise masses of glucose because the anaerobic glycolysis is 18 times more inefficient to produce ATP when compared to the aerobic metabolism. b. This low pH paralyses the immune response against tumour cells. c. In addition, tumour cells have carbon anhydrase enzyme CA IX is a hypoxia‐induced protein that is located at the cell membrane with an extracellular orientation. This enzyme converts CO2 into acid. d. Shifting metabolism away from mitochondria (aerobic glycolysis) and towards the cytoplasm (anaerobic glycolysis), suppresses apoptosis, a form of cell death that is dependent on mitochondrial energy production. This improves tumour cell survival. Simplified description of treatment of cancer 1.
Traditional therapy with radiation or chemotherapy Chemotherapy and radiation therapy disrupt the immunosuppression and the tumour matrix. This renders the tumour cells vulnerable to immune attacks. Tumour antigens from damaged tumour cells will enter the lymphatic system and can be phagocytized by dendritic cells and other antigen presenting cells (APCs). These APCs will present the antigens to the NKs (natural killer cells) and NKs will kill the tumour cells. The problem is that the high dosage of the traditional chemotherapy also destroys the immune system. Almost all tumour stem cells have MDR (multiple drug resistance) properties. This makes them invulnerable for chemotherapy. The first cycle of chemo wipes out the tumour matrix and generates unjustifiable high expectations. The composition of a regrown tumour after chemotherapy changes and has a higher proportion of tumour stem cells. The following cycles are predictably less efficient in reducing the tumour mass size. The traditional therapies are in general inefficient as tumour therapy. 2.
Additional therapies are not suitable as single therapy; they are meant to improve the tumour micro‐
environment to optimise immunotherapy or to increase tumour apoptosis. a. Anti‐inflammatory therapy to decrease the immunosuppression 
Frankincense 
Metformin 
Cimetidine 
Ezrin b. Anti‐inflammatory therapy to decrease the immunosuppression and apoptosis inducer 
Curcuma c. Tumour suppression disruption and tumour matrix disruption 
Low dose chemotherapy (for example gemcitabine, 10% of the normal dose) d. Metabolic shift toward aerobic glycolysis, tissue pH increaser, and apoptosis inducer 
DCA e. Tissue pH increasers 
Procaine based infusions and tablets f. Tumour apoptosis inducers 
Blue scorpion venom 
Vemurafenib: on‐going trials g. Miscellaneuos 
3.
Tyrosine kinase inhibitors: on‐going trials Immunotherapy and therapy with apoptosis inducers a. Dendritic cell therapy in combination with New Castle Disease Virus (NDV) as performed at the “Praxisgemeinschaft für Zelltherapie Duderstadt” 
In metastatic disease and in glioblastoma, response rate of 30‐40%, median 1 year survival of approximately 30%. It make sense to combine this treatment with anti‐immunosuppression therapy as described below. 
In postoperative colono‐rectal cancer with a non‐detectable disease on imaging after tumour removal: 100% response rate and 80% survival after 5 years b. Oncolytic viruses alone without dendritic cell treatment (measles and NDV): experimental phase c. Activation of macrophages 
gcMAF: no reliable results as mono‐therapy d. B‐RAF enzyme inhibitors 
Vemurafenib (Zelboraf; Genentech/Daiichi Sankyo), is a B‐Raf enzyme inhibitor. Aimed at melanoma patients with V600E mutated BRAF. 
Dabrafenib (Tafinlar; GSK) is a B‐Raf enzyme inhibitor. Aimed at melanoma patients with V600E mutated BRAF. e. Trematinib (Mekinist, xx) MEK1 and MEK2 (mitogen‐activated protein kinase kinase) inhibitor in melanoma patients with V600E mutated BRAF. f. Anti‐immunosuppression therapy: 
Cox‐2 inhibitors (to decrease the activation of MDSCs): on‐going trials 
Immune checkpoint inhibitors: 
a.
Opdivo (nivolumab, Bristol Mayers Squibb) anti‐PD‐1 monoclonal antibody: approved in Japan b.
Yervoy (ipilimumab, Bristol Mayers Squibb) anti‐body against CTLA4 receptors: approved by EMEA (Europe) and FDA (USA) for melanoma c.
Keytruda (pembrolizumab; MK‐3475, Merck) anti‐PD‐1 monoclonal antibody, approved by FDA for melanoma Escozin (blue scorpion venom): experimental phase References 1.
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