Malignant transformation October 11, 2011. Concepts of cell growth Growth of the body Renewal and repair Wound healing Cancer development.

Malignant Malignant transformationtransformation

October 11, 2011

Concepts of cell growth

Growth of the body Renewal and repair Wound healing

Cancer development

Concepts of cell growth

Proliferation Differentiation Apoptosis

Neoplasia menas „new formation“ Tumor means swelling

Proliferation

Permanent cells Stabile cells Labile cells

Cell differentiation

Increase of specialization decrease of ability to undergo mitosis

Stem cells – unspecialized cells surviving throughout life

Progenitor cells - partially specialized

Cell cycle

Interval between each cell division G1,S,G2,M phases Checkpoints – fidelity of DNA dupliaction

Benign and Malignant Neoplasms Malignant neoplasma: low level of

differentiation, invasive growth, high rate of growth, metastases

Tumor parenchyma x tumor stroma angiogenesis

Tumor neoangiogenesis

Dysequilibrium between antiangiogenetic and proangiogenetic factors („angiogenetic switch“).

Without neoangigenetic switch, the tumor growth is possible only to 1 – 2 mm3, when O2 and nutrients support is possible by difussion from surrounding tissue.

Hypoxia of tumor cells HIF- alpha induced transcription angiogenetic

factors

Invasiveness and Metastases

Invasion of the surrounding tissues, lack of sharp demarcation.

Metastases through lymphatic vessels, blood stream, dissemination in body cavities

Neoplasm growth

Exponential rate of growth Growth fraction Duration of cell cycle Cell death

Doubling time

Gompertz function

Etiology of cancer

Monoclonal theory of tumor origin Mutations in proto-oncogenes or tumor

suppressor genes (apoptosis regulation) Genes coding DNA repair systems – indirect

effect on oncogenesis Familial (inherited cancer) versus sporadic

cancer

Oncogenes

Derived from proto-oncogenes by mutations Proto-oncogenes are normal genes needed

for cell proliferation during growth, repair, replenishment of shed cells Growth factors genes GF receptors genes Protein kinases genes G proteins genes Transcription factors genes

Oncogenes

Mutations in proto-oncogenes are dominant i.e. one copy of the oncogene (mutated proto-

oncogene) is sufficient to provoke tumor cell transformation

Tumor suppressor genes

Inhibit cell proliferation Suppressor genes are recessive i.e. one

normal copy is sufficient to block tumor cell transformation

Inherited cancers e.g. RB gene

Tumor parenchyma x tumor stroma Tumor parenchyma – transformed cells with

mutated DNA Tumor stroma – cells with

normal genetic information

Factors of carcinogenesis

Heredity RB, BRCA-1, BRCA-2

Hormones Genital tract tumors

Immunologic mechanisms Immune surveilllance hypothesis Tumors in immunocompromised patients (e.g. AIDS

and Kaposi sarcoma) Chemical carcinogens

1775, scrotal cancer in chimney sweeps Industrial exposure Food and drugs

Ionizing radiation Stochastic effects

Oncogenic viruses Only a few of viruses is directly linked with cancer

in humans HPV, EBV, HBV, HTLV-1

Monoclonal origin of the tumor Most human neoplasms are monoclonal in origin, i.e. they arise from

genetic mutations within a single affected cell; however, over subsequent divisions heterogeneity develops through the accumulation of further abnormalities.

The genes most commonly affected can be characterized as those controlling

cell cycle check points, DNA repair and DNA damage recognition, apoptosis, differentiation, and growth signaling. Proliferation may continue at the expense of differentiation, which

together with the failure of apoptosis leads to tumor formation with the accumulation of abnormal cells varying in size, shape and nuclear morphology as viewed down the light microscope.

Cancer genetics The development of cancer is associated with a fundamental genetic change

within the cell. Evidence for the genetic origin of cancer is based on the following:

Some cancers show a familial predisposition. Most known carcinogens act through induced mutations. Susceptibility to some carcinogens depends on the ability of cellular enzymes to

convert them to a mutagenic form. Genetically determined traits associated with a deficiency in the enzymes

required for DNA repair are associated with an increased risk of cancer. Some cancers are associated with chromosome 'instability' because of

deficiencies in mismatch repair genes. Many malignant tumors represent clonal proliferations of neoplastic cells. Many tumors contain well-described cytogenetic abnormalities, which involve

mutated or abnormally regulated oncogenes and tumor suppressor genes with transforming activity in cell lines.

Mutations may occur in the germ line and therefore be present in every cell in the body, or they may occur by somatic mutation in response, for example, to carcinogens, and therefore be present only in the cells of the tumor.

Cancer genetics

Expression of the mutation and hence carcinogenesis will depend upon the penetrance (due to level of expression and presence of other genetic events) of the gene and whether the mutated allele has a dominant or recessive effect. There are a small group of autosomal dominant inherited mutations such as RB (in retinoblastoma) and a small group of recessive mutations.

Carriers of the recessive mutations are at risk of developing cancer if the second allele becomes mutated, leading to 'loss of heterozygosity' within the tumour although this is seldom sufficient as carcinogenesis is a multistep process.

Cancer genetics

Malignant transformation may result from a gain in function as cellular proto-oncogenes become mutated, (e.g. ras), amplified (e.g. HER2), or translocated (e.g. BCR-ABL). However, these mutations are insufficient to cause malignant transformation by themselves.

Alternatively, there may be a loss of function of tumour suppressor genes that normally suppress growth and differentiation. A third mechanism involves alterations in the genes controlling the transcription of the oncogenes or tumour suppressor genes (e.g.

Malignant transformation of the Malignant transformation of the cellscells Cell division is carefully controled to serve to actual

needs of the organism. Early in life, cell division capacity outweighs their

destruction, in adulthood, it is in dynamic equilibrium and in senescence, involution dominates.

Some cells are able to obviate the replication control.They change their phenotype to tumor ones.

Benign tumor cells Malignant tumor cells (invasivity, metastatic

potential).

Malignant transformation of the Malignant transformation of the cellcell Malignant tumor is a genetic disease It starts in one cell Usually a multistep process with Increasing number of alterations of genes

controlling proliferation, diferenciation and destruction of the cells.

Clonal progressing of tumor cells1. mutation 2. Cells with mutation 1 and 2 gradually overgrow and/or displace cells

with only mutation 1. 3. Next mutations cause the growth of more and more aggressive

populations of the cells. 4. Subclonal genetic heterogenity of the tumor is a recoil of the

progressing development of the tumor

Malignant transformed cells Continue their division. Needs for presence of hormones and growth factors

decreased. Production of own growth factors (autokrinnal stimulation). Decrement of ability to stop the growth. Decreased ability to stop the growth in worse nutrition

conditions-

Malignant transformed cells Occur most frequently in the tissues with quick

proliferation, especially when the influence of kancerogenes and hormones is present.

Environmental factors have a great impact on gene expression ot the target cells

A plenty of signals accepted by the cell leads to activation of specific transcription factors which decide about either

division or difecenciation or apoptosis

Process of cancerogenesis Tři stádia: (1) Initial stadium, =mutation of critical gene.

(2) Promotion stadium (years); Transformed cells are stimullated to even more intensive proliferation.

Promotion factors are not able to initiate malignant transformation, only to give support to it.

Process of cancerogenesis

(3) Progression stadium - increased number of gene changes leading to

(a) uncontroled growth due to permanent activation off signal transduction of growth stimulus,

(b) alteration of check points of cell cycle (c) deregulation of DNA- transcription factors. Invasion Matastasis Tumor neoangiogenesis.

Tumor phenotype

Is characterised by the process of malignant transformation of the cell with- loss of control of cell division (alterations in cell cycle, antiapoptotic state, „immortality „ of tumor cell, alteration in signal transduction),- loss of cell-cell contant inhibition, invasivity,- changes in metabolism- proangiogenetic activation

Malignant transformed cells seem to be resistent to external stress factors as hypoxia, low pH, hypoglycemia, malnutrition.

Metastatic phenotype Loss of dependence to adhere to substrates

(tumor cells are able to divide even in tissue culture)

Loss of gap junctions. Changes in cell membrane (glycolipids and

glycoproteins modifications).

Metastatic phenotype Increased motility, invasion and ability to form

metastases. Increased production of receptors (adhesive

molecules) Increased production of hydrolytic enzymes Function of chemokines

Tumorigenesis

Phenomenon of tumor suport Chemical cancerogenes: Initiators: compounds with cancerogenic

potential after their metabolisation (P450). Promoters: effects possible after initiators

(phorbolester).

Tumor-supresor protein p53 (TP53) Is a nuclear protein with key role between

G0 and G1 phase of the cell cycle. Mutant variants of the p53 gene can be found

in many cancer types. Somatic mutations Germ mutations (syndrome Li-Fraumeni).

Tumor genotype

Mutations in proto-onkogens tumor-supressor genes Genes for genome stability Genes modifiers.

Proto-onkogenes and oncogenes

Up to 100 of various human protooncogenes in each somatic cell.

Targets for transduction signals (mitogenic), by which their expression is regulated

Proto-onkogenes and oncogenes Mutations of proto-oncogenes changes them

to oncogenes. Dominant mutation. Different pathways of proto-oncogenes

activation: (a) viral transduction (e.g. onkogene src) (b) gene amplification (myc, abl), (c) viral insertion (myc) (d) chromosomal alteration (myc, abl) (e) mutation (ras) 

Types of oncogenes They are classified to 5 classes: (1) growth factors (2) growths factors receptors (3) intracellular transducers of the signals (4) nuclear transcription factors (5) proteins controlling cell cycle

Apoptosis and tumorigenesis

Overexpression of Bcl2 (B-cell lymphoma 2) gene was found to be related to inhibition of apoptosis during tumorigenesis.

Tumors and immortality of cells

Increased activity of telomerase. Telomers are key stabilisation factors of terminal part of

the chromosome. Telomeres have repetitive sequence TAGGG. The length of telomers is decreased after multiple divisions

of the cell (1 cell cycle is shortening of 1 telomere). Their renewal is catalysed by telomerase. Two mechanisms during tumorigenesis: mechanismus TERT („telomerase reverse transcriptase“)„alternative lengthening of telomere (ALT) pathway“),