Pathophysiological pathways of Tumor Growth

Pathophysiology department, faculty of Stomatology, 29.09.2011

Design of lecture
1. 2. 3. 4. 5. 6. 7. 8. 9.
Typical forms of cell growth disturbance Definition of Tumor Growth Etiology Risk factors Pathogenesis of Tumor growth Major features of cellular growth regulation Molecular mechanisms of cancer Neoplastic atipisms (Anaplasia) Antineoplastic resistance

Glossary
1.
2.

Neoplasia –new growth
Tumor are named according to the tissue of origin with the suffix “oma” added

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“Cancer” – refers to a malignant tumor
Tumor cell markers –are substances that are produced by cancer cell and found on tumor plasma membranes or in the blood spinal fluid, urine (they include hormones, enzymes, genes, antigens, antibodies) Oncogenes – are genes that can transform a normal cell into a cancerous Proto-oncogenes – are normal genes, that regulate growth and development by encoding for growth factors (GF) and GF receptors

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Glossary
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Heterozygosity – loss of one gene copy Transformation – the process by which a normal cell becomes a cancer cell Anchorage independent – they can continue to divide in a soft agar gel Autonomy – refers to the cancer cell’s indepence from normal cellular controls Autocrine stimulating – the ability to secrete GF that stimulate their own growth Epigenetics – that don’t involve changes in DNA sequence

Neoplasia
Definition 1. A tumor is an abnormal mass of tissue, the growth of which is virtually autonomous and exceeds that of normal tissues (by Robbins) 2. A tumor is abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and persists in the same excessive manner after the cessation of the stimuli, which avoke the change (by Willis) 3.Cancer is a disease of abnormal cell growth, division and cell proliferation (by McCance, S. Huether)

Memory check !

Cell cycle
1) The reproduction or division of somatic cells involves two sequential phases:  mitosis (nuclear division) and interphase  cytokinesis (cytoplasmic division)   Beginning toward the end of mitosis

Memory check !
2) Before a cell can divide, it must double its mass and duplicate all of its contents. Most of the preparation for division occurs during the growth phase (interphase)

Memory check !
3) There are four designated phases of the cell cycle: I. The S phase (synthesis) – in which DNA is synthesized in the cell nucleus II. The G2 phase, in which RNA and protein synthesis occur III. The M phase (mitosis) which includes both nuclear and cytoplasmic division IV. G1 I phase, which is the period between the M phase and the start of DNA synthesis  Interphase, which consists of the G1, S and G2 phases, is the longest phase of the cell cycle.

Memory check !
4) Gene and protein growth factors govern the proliferation of different cell types  Cells require highly specific proteins to stimulate cell division. These growth factors are present in the serum in very low concentration (for example platelet-derived growth factor stimulates the production of connective tissue cells, or interleukin which stimulates the proliferation of T-cells)  Cells have specific receptors for the specific growth factor in their plasma membrane. Some growth factors are also regulators of cell differentiation.  It is likely that some genes code for growth factors, some for receptors, some for intracellular regulatory proteins, some for proteins that help relay signals for cell division to the cell nucleus

Epidemiology
General facts  Cancer is the second leading cause of death in the United States and other countries  Estimated number of new cancers in 2005 (1.372.910)  Estimated number of deaths from cancer in 2005 (570.280)

Etiology
Carcinogenic Agents
1. 2. 3. 4. 5.

Chemical carcinogenes Radiation (physical) Oncogenic viruses, bacterial cause Role of inflammation, immunity in cancer Loss of immune regulation and chronic inflammationn (parainflammation)

Chemical agents
1. Clinically important chemical carcinogenic
a. b. c. d. e. f. Polycyclic Aromatic hydrocarbons: present in cigarette smoke Azo dyes: β-naphtylamine, aniline Nitrosamines and amides (synthesized from nitrites in GIT) Naturally occurring carcinogens (aflatoxin produced by the fungus aspergillus flavus on moldy grains, peantus) Alkalating agents Miscellaneous agents: Asbestos, vinyl chloride, metals (nickel), arsenic, benzene, beryllium, cadmium, chromium component, ethylene oxide Hormones (estrogen) Free radicals

g. h.

Chemical carcinogenesis
• Carcinogenesis is multistep process involving a sequence of initiation (mutation) followed by promotion (proliferation) and progression • Initiators: direct acting, non-direct acting chemicals • Promotors - cause cellular proliferation of mutated (initiated) cells. Proliferation may lead to accumulation of additional mutations • Tumor progression – appearance of subpopulation which differ with respect to several phenotypic attributes

Human viruses associated with cancer
Virus family Types

1. Hepatitis viruses
2. Herpesviruses

Hepatitis B
Epstein-Barr KSHV/HHV-8 is linked to immunodeficiency HPH-16, HPV-18,31-other HTLV-1 Hepatitis C

3. Papillomaviruses 4. Retroviruses

Viral and microbial carcinogenesis
DNA-viruses • HPV (human papilloma virus) • Epstein-Barr viruses (EBV) • Hepatitis B virus(HBV) • HPV cause benign squamous (warts)in human, supporting role in human cancers (cervical cancers) anogenital Epstein-Barr viruses (EBV-member of the herpes virus family) is associated with four human cancers: a. Burkitt lymphoma, b. Nasopharingeal cancer, c. B-cell lymphoma in immunosuppressive patients (AIDS), d. Some forms of Hodgkin disease. Kaposi sarcoma- associated withherpesvirus (HHV8) Hepatitis B virus (HBV)-hepatic cancer, hepatocellular carcinoma

C virus RNA viruses human oncegenic retrovirus is Human T-cell lymphotropic virus type 1 (HTLV-1) Linked to the T-cell Leukemia/lymphoma Hepatitis C virus Bacterial cause cancer (microbial factors)

HP helicobacter pylori induced Gastric ulcer and carcinoma
It is also associated with gastric lymphomas Mechanism: H. pylori infection induces methylation of specific genes in the gastric mucosa.

Physical factors
•Radiation (Carcinogenesis)
• Ultraviolet Rays (sunlight) –Ionizing radiation – X- rays, - rays, -, - particles, protons, neutrons

Effects: transcriptional errors and mutations

Risk factors

Gender: In man cancer of lung, colon and prostate are the

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leading causes of cancer death; in woman- breast, colon, lung are most common forms Geographic and Environmental factors: Japan-the death rate from cancer of the stomach 7 times that in England, USA Cancer of the breast in England, USA rate increases, but in Japan decreases Carcinoma of colon is much less common as a cause of death in Japan Increased risk of certain cancers with exposure to asbestos, alcohol vinyl chloride, 2-naphtylamine Association of carcinoma of the or pharynx, larynx, and lung with cigarette smoking

Risk factors

Age: Cancer is most common in those older than 55
years of age, certain cancers are particularity common younger than 15 years of age:  Leukemia and lymphomas Tumor of the hematopoietic system Neuroblastoma Wilm’s tumor Retinoblastomas Sarcomas of bone and skeletal muscle


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Risk factors
I. Heredity:
1. Inherited cancer syndrome (inheritance by single mutant genes, autosomal-dominant trait): a. familial retinoblastoma,

b. familial adenomatous polyposis
c. multiple endocrine neoplasia 2. Autosomal recessive syndromes of defective DNA repair Chromosome DNA instability Increased by environmental carcinogens. II. Acquired preneoplastic disorder; (clinical conditions which are associated with an increased risk of developing cancers)

• Cirrosis of liver-hepatocellular carcinoma • Atrophic gastritis or pernicious anemia - stomach cancer • Chronic ulcerative colitis - carcinoma of the colon • Leukoplakia of the oral and genital mucouse - squamous cell cancers • Certain benign tumor (e.q. village adenomas of the colon )

NOTE! (inflammation, immunity, and cancer)
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2.

Chronic inflammation (and more specifically parainflammation) has been recognized as being an important factor in the developments of cancer (ex. sialedenits → salivary gland carcinoma) Although the immune system is indeed important in protecting us against cancers caused by specific viral infections, it does not effectively protect us against most common cancers (breast or prostate lung, colon cancer).

Characteristics of neoplasma:
Differentiation  (loss) and anaplasia  Pleomorphism (variation size)  Hyperchromasia  High N/C (nucleous/cytoplasma) ratio (normal 1:4-1:6)  Disturbed orientation  Displasia – loss in uniformity of individual cells and less in their architectural orientation  Anaplasia (hallmarks of cancer cell) ↓ The loss of cell differentiation, irregularities of the size and shape of the nucleus, and loss of normal tissue structure.

Classification
Due to on the characteristic of their parenchyma Benign Malignant

1. 2. 3. 4.

Based on 4 criteria Differentiation and anaplasia Rate of growth Local invasion Metastases

Comparison Rate of growth and local invasion
Benign: slow growing, cohesive, expansive capsule Malignant: Autonomy,Infiltration, Invasion, destruction, and metastasis Most reliable feature of malignancy – is the Metastasis 2nd most reliable feature – Invasiveness

Cancer cells are defined by two heritable properties: 1. autonomy and 2. anaplasia (literally “without form”) 1. Cancer cells independence from normal cellular control 2. Is a loss of differentiation

Cancer cells has lost its ability 1) to function normally 2) to control its growth and division

PATHOGENESIS OF NEOPLASIA
The Molecular Basis of Cancer is a non lethal genetic damage!

The target molecules are:
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Proto oncogenes → Oncogenes Tumor suppressor genes Telomeres/reactivation of telomerase Apoptosis prevention gene Caretaker genes (DNA repair)

Carcinogenesis
Carcinogenesis multistep process: Four classes of genes are the targets of genetic damage:
Growth-promoting proto-oncogenes (oncogenes) II. Growth-inhibiting tumor-supressor genes III. Genes that regulate apoptosis IV. Genes that regulate DNA repair
I.

General :

• •

Activation of growth promoting Inactivation of Tumor suppressor genes Disregulation , Resistance to apoptosis

Pathogenesis of Tumor
Carcinogenesis is a multistep process 2. Development of C. requires the accumulation of multiple genetic changes: Inherited germ line mutation Acquired mutation 1. Tumor is derived from monoclonal expansion of mutated cell 2. Host important mutations in: a. Growth promoting genes (protooncogenes) b. Growth inhibiting tumor suppressor genes c. The genes regulating apoptosis
1.

Cell cycle regulation

The sequence of events that characterize normal cell proliferation
Under physiologic conditions all proliferation can be readily resolved into the following steps:  The binding of a growth factor to its specific receptor on the cell membrane  Transient and limited activation of the growth factor receptor, which in turn activates several signal transduction proteins on the inner half of the plasma membrane  Transmission of the transduced signal across the cytosol to the nucleous via second messengers  Induction and activation of nuclear regulatory factors that initiate DNA transcription  Entry and progression of the cell into the cell cycle resulting ultimately in cell division

Gentetic disturbances of any of the above leads to transformation.

Transformation due to genetic disturbance of: Normal Cell • • • • Growth factors Growth factor’s receptors Signal transducting Regulation transcription •Transformed proliferation •Abnormal and autonomy regulation of growth •Disturbance of replication

Tumor Cell

Pathogenesis of cancer
Acquired environmental factors: chemical, radiation, viruses

Normal cell
DNA damage

Genetic factors inherited mutations in genes affecting Cell growth or DNA repair

Mutations in the genome of somatic cells
Activation of growth promoting oncogens Alteration of genes that regulate apoptosis Inactivation of cancer suppressor genes

Expression of altered gene product and loss of regulatory gene products

Oncoproteins
Clonal expansion Additional mutation (progression) Heterogenity

Malignant Neoplasm

I. Activation of protooncogen oncogens
Protooncogenes are normal cellular genes involved with growth and cellular differentiation 1. Oncogenes are derived from protooncogenes by either a. A change in the gene sequence, resulting in a new gene product (oncoproteins) b. Loss of gene regulation resulting in overexpression of the normal gene product 2. Mechanisms of oncogene activation a. Point mutation b. Chromosomal translocation c. Gene amplification(reduplication of oncoproteins) d. Insertions, deletions e. Gene silencing (DNA methilation, histone modification) f. Exogenous sequences (tumor) viruses

Pathogenesis of Tumor

Epigenetic mechanisms in the pathogenesis of tumor growth: gene silencing
“Turning off” genes without mutation (epigenetic silencing – is caused by reversible chemical modification – methylation, acetylation of histones, DNA methylation ets.)

Protein products of oncogenes
1. 2. 3.

4. 5.

Growth factors Growth factor’s receptors Signal transducting proteins (guanosine GTPtriphosphate binding proteins and non-receptor associated tyrozine kinase) Nuclear transcription proteins (mus,jun,fos) Cyclins and cyclin - dependent kinases regulate the progression of cells through the cell cycle
Note! Activated oncogenes lack regulatory control and

are over expressed, resulting in unregulated cellular proliferation

Pathogenesis of Tumor
II. Inactivation of tumor suppressor genes (TSG)
Rb WT-1, - 2 Retinoblastoma Wilm’s TUMOR

p53 APC
BRCA -1 NF-1, -2

Lung, breast, colon etc. Adenomatous polyps and colom cancer
breast cancer neurofibromas, neuromas

Pathogenesis of Tumor
TSG

encode proteins that regulate and suppress cell proliferation by inhibiting progression of the cell through the cell cycle.  Mechanisms of action of some tumor suppressor genes.
a. P53 prevents a cell with damaged DNA from entering S-phase b. Rb prevents the cell from S-phase until the appropriate growth signals are present

III. Impairment of the regulation of Apoptosis
1. Over expression of Bcl-2 - prevent apoptosis (in follicular lymphomas) 2. Low expression, blocked genes promoting apoptosis bax, bad, bcl-xs, bid 3. Mutation of p53 promotes apoptosis in mutated cell by stimulation bax synthesis 4. c-myc promotes cellular proliferation   when associated with p53 leads to apoptosis  when associated with Bcl-2 inhibits apoptosis

Role of telomerase

Senescent postmitotic cell

Tumor
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IV. Telomeres/telomerases
ATTENTION! Other than germ cells, body cells couldn’t unlimited divided, because of regulation by telomeres. There are control the activity of chromosome. Telomeres are protective ends or caps and become smaller with each cell division. Short telomeres normally signal the cell to cease cell division. Cancer cells, when they reach a critical age, activate telomerase, which restore and maintain telomeres  resulting in to divide over and over again  immortality of cancer cell. Shortening of telomere take place after each division of cell. In tumor cells due to specific enzymes telomerases telomeres are permanently recovered. So, there is unlimited division of cell.

V. Disorder of DNA repair Caretaker genes mutations

Growth of the tumor and its transformation

Progression of the tumor

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Main hallmarks of cancer

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Increase self – production in growth signals – autocrine regulation Inactivation of antigrowth signals Resistance (evading) to apoptosis Limitless replicative potential Sustained angiogenesis Tissue invasion and metastatis + Warburg effects ?

Metastatic avenues/sequence
Neoplastic cell multiplication and local invasion Penetration Lymphatic Blood vessels Cellular growth Efferent lymphatic entrance

Cellular death
No neoplasm

Extravasations
Organ tropism New growth site

Metastatic neoplasm

Angiogenesis

Angiogenesis
Cancer needs blood/supply to deliver O2 and nutrients. Cancer has ability to grow new blood vessels. Cancer can secrete factors that stimulate new blood vessel growth → angiogenesis. Example of angiogenic factor is vascular endothelial growth factor (VEGF) (other factors).

1. Abnormality of proliferation
b) Loss of proliferation limit,

Biological properties of benign and malignant tumors (Activisms)
a) unregularity of proliferation,

2. Abnormality of differentiation 3. Abnormality of metabolism and energy production
a) Tendency to anaerobic glycolysis (Warburg effect) Increased production of oncoproteins, b) Synthesis of embryonic proteins, c) Change of resynthesis of energy, d) Phenomenon of metabolic traps (glucose, aminoacids), e) Decrease concentration of c-AMP and increase concentration of cGMP,

4. Physico-chemical abnormality (K+, Ca2+) 5. Antigenic abnormality (iso, transplatatory, embryonic, hetero)

Biological properties of benign and malignant tumors (Atipisms)
6. Morphologic abnormality 7. Abnormal functioning a) Inhibition of functions, b) Increase of functions, c) Disturbance of functions 8. Abnormal tumor cell-to-host organism interaction a) immunodepression, b) Ectopic endocrine syndromes c) Influence of stress, d) Cardiovascular insufficiency e) Muscular dystrophy, f) Amino acid, energetic, antioxidative, vitamine and other deficits

Antineoplastic resistance of organism
1. Anticarcinogenic (inactivation, elimination, pinocytosis, interferon, antibodies, antioxidants) 2. Antitransformational (DNA repair enzymes, antioncogenic mechanisms) 3. Anticelular (specific and non specific, immune protection, TNF, IL-1, allogen inhibition by the normal cells, keilons:tissue specific mitogen supressors 1 –lipoprotein  cancerolysis, contact inhibiting, cAMP+, cGMP-, labrocytosis, increase of humoral protection) Pathways of increase antineoplastic resistance Activation of apoptosis Immunotherapy Photodynamic therapy Biotechnology

Typical Test
1. Choose the correct definitions: a) A tumor is an abnormal mass of tissue, the growth of which is virtually autonomous and exceeds that of the normal tissues b) Cancer is a disease of abnormal cell growth, division and cell proliferation c) Tumor is a increase of a number of cell d) Tumor is a hyperplasia and hypertrophia of tissue I. a,c II. b,d, III. a,b IV. a,b,c,d
2. All the following are causes of tumor, EXCEPT: a) Epstein-Barr viruses b) HTLV-1 c) Megaloviruse d) Hepatitis B-V e) Human herpes viruses

3. All the following are the chemical causes of cancer, EXCEPT: a) Asbestos b) Vinyl chloride c) PgE1 d) Arsenic e) Benzene 4. All the following are the cancer-induced DNA-viruses, EXCEPT: a) HPV b) EBV c) HBV d) HTLV-1 e) HHV8

5. Which are the endogenous carcinogenic chemicals: a) Free radicals b) Aflatoxin c) Vinyl chloride d) Estrogen I. a,b II. b,c III. c,d IV. a,d
6. Warburg effect is manifested by: a) Activation of growth promoting protooncogenes b) Activation of antioxidants c) Increased oxygen consumption d) Activation of anaerobic glycolusis

7. Which of the following suppressor gene is related with apoptosis: a) Rb b) p53 c) APC d) NF-1 I. a,b II. b,c III. c,d IV. a,d
8. Choose the four classes of genes, which are the targets of tumor growth a) Genes that regulate DNA repair b) Genes that regulate adhesion molecules synthesis c) Genes that regulate apoptosis d) Inhibiting genes e) Protooncogens I. a,b,c,d,e II. a,b,c III a,c,d,e IV. c,d,e

9. Which of the following about mechanisms of oncogene activation is false: a) Point mutation b) Chromosomal translocation c) Amplification d) Insertion of mutagens e) DNA repair 10. False statement about tumor suppressor gene is: a) TSG encode proteins that regulate and suppress cell proliferation b) p53 prevents a cell with damaged DNA from entering S-phase c) Rb prevents the cell from S-phase until the growth signals are present d) TSG encode proteins of growth receptors

11.Biological properties of tumors are following a) Immunodepression b) Antioxidant’s deficit c) Increase concentration of cAMP d) Decrease concentration of cGAM e) Phenomenon of metabolic traps. I. a,b,c II. d,e III. a,b,c,e 12. All the following are antineoplastic resistance , EXCEPT: a) Antioxidants b) Decrease of cAMP c) Allogen inhibition d) Labrocytosis

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