Cancerogenesis

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As many as 350 billion mitoses occur in each person every day. With each cell division there is a possibility that both resulting cells will be malignant. Yet very few cancers actually develop in any individual. Cells capable of forming cancers develop at certain frequency but a majority are never able to form observable tumors. The reason is that a solid tumor, like any other rapidly dividing tissue, needs O2 and nutrients to survive. Without a blood supply, potential tumors either die or remain dormant. When dormant, such ‘microtumors’ remain a stable cell population wherein dying cells are replaced by new cells.


Most victims of cancer do not die from the original cancer but from numerous metastases. To enter a blood vessel a tumor cell has to lyse the collagenous matrix surrounding the new capillaries, and that is done by secretion of plasminogen activator, a proteolytic enzyme, very similar to that assuring the implantation of blastocyst into the uterine wall.


Mitosis is precisely adapted to the actual needs of cells by a local release of growth factors. Besides mechanisms that increase proliferation there are factors that decrease growth via interruption of excessive mitosis. Mutations of relevant proliferation genes can lead to the development of oncogenes, the products of which called oncoproteins are active even without physiologic stimulators, and can trigger mitoses independently of physiologic growth factors.


Mutations can be caused by viruses, chemicals, radiation, etc., and malfunctions of DNA repair mechanism support their continuation. Cells are prone to mutations particularly during mitosis, i.e. proliferating tissue is subject of mutations more often than differentiated tissue. This happens particularly with tissue inflammation and tissue lesions due to injuries, and in both situations mitosis is stimulated.


One mutation is not sufficient for creation of cancer, only multiple mutations can cause degeneration of normal cell into a cancer cell. For malignant transformation is not enough one mutation, but a cascade of genetic events one after another.


Oncogenes can be brought into the host cell by viruses.


Uncontrolled cell division brings on gradual dedifferentiation. Dedifferentiated cells are often recognized and eliminated by the immune system unless it is weakened, such as due to HIV-infection. On the other side cancer cells can express on their surfaces CD95+ receptor and binding of lymphocytes to such receptor causes the apoptosis and thereby weakening of immune system.


Proliferation of cancer cell leads to the creation of tumor. Markedly dedifferentiated tumors are able to create metastases. For that to happen the cancer cells must get separated from their ‘mother’ colony, i.e. be capable to migrate and break tissue barriers, penetrate into blood vessels, leave blood circulation in another organ by binding to the specific adhesive molecules of endothel and penetration of blood vessel wall, and finally create a new colony in the other organ.


Tumor growth, or metastases, require adequate capillary network in order to get adequate quantity of oxygen and nutrients. Angiogenesis is stimulated by mediators, or limited by inhibitors.


Energy needs of cancer cells are covered by glycolysis even with adequate supply of O2 so that one mol of glucose generates only 5% of energy that could be obtained via Krebs cycle. This results in hypoglycemia and acidosis. Hypoglycemia stimulates release of glucagons, adrenalin and glycocorticoids which support breakdown of fats and proteins, and that leads to cachexia. Some cancer cells cause activation of coagulation, or fibrinolysis, production of abnormal antibodies, hormones, etc., that further disrupts homeostasis. Massive cancer cells death leads to the release of intracellular K+ and hyperkalemia, and to breakdown of nucleic acids with hyperuricemia.


Cancer is a genetic disease on a somatic cell level.


There are aberrations of various kinds on all chromosomes in solid tumors as well as in disseminated hematological malignancies. Majority of these are rare, some occur commonly, while some are found more frequently in certain kinds of tumors and represent ‘markers’.


Here is an attempt at classification :


1/single-gene cancer determinants:

- single gene disorders with increased risk of malignant growth, about 100 – 150; - genetic cancers, such as bilateral retinoblastoma, familial melanoma, multiple endocrine adenomatosis, i.e. Zollinger-Ellison syndrome, Sipple syndrome; - pre-cancerous conditions:

a/ phacomatoses: neurofibromatosis, tuberous sclerosis, v.Hippel-Lindau syndrome,</div>

b/ polyposes syndromes : polyposis coli familiaris, Gardner syndrome,</div>

c/ multiple exostoses,</div>

d/ diseases of defective DNA repair mechanism : xeroderma pigmentosum, Bloom syndrome, ataxia teleangiectasia, Fanconi pancytopenia;</div>

2/ Multifactorial predisposition toward cancer, such as with breast cancer, stomach cancer, uterine cancer, leukemias;

3/ Association of chromosomal aberrations with increased risk of malignancy:

- Down syndrome, with leukemoid reactions, and myeloid leukemia, - Syndrome of chromosomal instability, - Association of specific chromosomal aberrations with cancer, e.g. Ph chromosome and chronic myeloid leukemia, reconstituted chromosome aberrations, reconstitution in the proximity of dominant oncogenes;

4/ Molecular oncogenesis: - oncogenes as triggers of AD disorders, - mutator-genes, AR disorders: cancer cells are characterized by general genetic instability, with abnormal karyotypes, often of bizarre type, with multiple deletions, duplications, and chromosomal re-structuring, and the responsibility for this lies with mutator-genes the function of which is to secure integrity of genetic information: their malfunction causes non-effective DNA replication or non-effective repair. - ‘oncogene viruses’ can cause cancer development in experimental animals, as was proven decades ago with the virus of Roux sarcoma in chicken.


After their entry into the cell, these RNA-viruses transcribe their RNA-genom with help of reverse transcriptase into chromosomal DNA of the host, and so secure the replication of virus.


Oncogene viruses play role in 15% of human cancers. RNA-oncogene viruses cause T-cell leukemia in adults (HTLV-1, HTLV-2) and Kaposi sarcoma. DNA-oncogene viruses cause cancer of uterine cervix (papilomavirus HPV16), nasopharyngeal cancer (Epstein-Barr virus), hepatocellular carcinoma in South-East Asia, and tropical Africa (hepatitis B virus).


There are additional genes in such viruses in all mammals, including man, calledProto-oncogenes, which turn into oncogenes in the course of preceding viral infection. The main function of protooncogenes under physiologic circumstances is the regulation of cell cycle, cell proliferation and specific differentiation of normal cells.


But also the creation of solid cancers depends on oncogenes, i.e. RAS oncogene is found in sarcomas, neuroblastoma, retinoblastoma, melanoma, lung cancer, cancer

of urinary vesicle, breast cancer, but also leukemias and lymphomas.


SIS oncogene is found in osteosarcomas, fibrosarcomas, gliomas, breast cancer. ERB-B is found in squamous carcinoma, adenocarcinima of salivary and mammary

gland.


-tumor suppressive genes, AR disorders: While the oncogenes trigger the start of cancerogenesis actively, tumor suppressive genes do so passively by being inactive. While oncogenes are effective even in heterozygote state, i.e. they are dominant genes, with tumor suppressive genes one normal allele is sufficient guardian against the development of cancerogenesis, i.e. they are recessive oncogenes.


Mutation of Gene TP53 is the most frequent genetic damage found in cancer. It is known as ‘guardian of genome’. Product of gene TP53, i.e. protein p53, is active during the cell mitosis. It slows down the mitotic cycle before the beginning of S-phase so that the repair enzymes have enough time to repair any damage due to the mutation and thereby prevents a completion of mitosis which would allow transfer of damaged DNA to the daughter-cells.


The first malignant disease with a specific chromosomal aberration was chronic myelogenous leukemia. This disease is characterized by a long preleukemic phase, during which there is already a myelopoietic disturbance, but without any findings in blood. Dramatic turn into acute myeloid leukemia, i.e. myeloblastic crisis, can happen suddenly and unexpectedly. Typical cytological finding is a small eccentric ‘Philadelphia chromosome’, which in adult type of this disease in found in 90% of patients, while in 80% of children is absent.


Burkitt lymphoma is a common tumor in tropical Africa, predominantly of children. Specific chromosomal aberrations were found in cancer cells..


Acute lymphoblastic leukemias in children, acute promyeloid leukemia, non-Hodgkin lymphomas, are also characterized by specific chromosomal aberrations.


‘Two hits hypothesis’ is currently the leading theory of development of hereditary solid cancers. The examples are:

1/ Familial hereditary retinoblastoma is a bilateral cancer of retina with incidence 1:20000, where the first hit is mutation of RB1 gene in gametes of parents: this is found in all cells of the child and is inherited as AD disorder with incomplete penetration; 50% of offsprings/heterozygotes has predisposition for retinoblastoma. For the creation of a cancer a ‘second hit’ is necessary, and that is a mutation of the second RB1 gene in the target somatic cell of retina.

2/ Breast cancer is inherited in 7% of cases;

3/ Li-Fraumeni syndrome, AD disorder with incidence 1:50000, with high risk of development of cancer: by 30 years of age the penetration is 50%, by 60 years it reaches 90%; patients get sarcomas of connective tissue, osteosarcomas, brain tumors, adrenocortical cancers, breast cancer;

4/ Wilms tumor is the most common solid tumor of children with incidence 1:10000. It is diagnosed by the age of 30 months as an isolated disease, or a part of the following syndromes: WAGR (Wilms tumor, aniridia, urogenital anomalies, mental retardation), Denys-Drash syndrome (Wilms tumor, urogenital anomalies, glomerulonephropathy), Beckwith-Wiedeman syndrome (Wilms tumor, omphalocele, macroglossia, gigantism).

5/ Neurofibromatosis, type 1 (v. Recklinghausen disease) with incidence 1:3500, with high predisposition toward cancer: glioma of optic nerve, neurofibroma, astrocytoma, neurofibrosarcoma, osteosarcoma, Wilms tumor. There are multiple benign neurofibromas, bone anomalies, mental retardation, café-au-lait spots; type 2 is AD disorder with 95% penetration, with incidence 1:50000, characterized by bilateral acoustic neurinomas with headaches, deafness, tinnitus, facial paralysis, mental disturbances.

6/ Familial adenomatous polyposis of colon is AD disorder, with mucosa of colon covered by hundreds to thousands of polyps/adenomas, pre-cancerous, one of which invariably turns into cancer.