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Plan of the lecture

1. 2. 3. 4.

5.
6. 7.

8.

Neoplastic growth. Definition. Features of benign and malignant tumors. Classification of cancerogens. Pathogenesis of tumors. Stages of cancerogenesis. Characteristic of tumor cells. Mechanism of immunological response against tumor cells. Treatment of tumors.

Actuality of the lecture


By the prognoses of Worldwide health protection organization morbidity and death rate from oncologic diseases in the whole world will grow in 2 times for period from 1999 year for 2020: from 10 to the 20 million new cases and from 6 to the 12 million registered deaths. Taking into account that in the developed countries there is a tendency to deceleration of growth of morbidity and death rate from malignant tumors (due to the prophylaxis and due to the improvement of early diagnostics and treatment), clearly, that a basic increase will be at developing countries (countries of former USSR). That is why doctors have to expect serious increase of morbidity and death rate from oncopathology. From data of Committee of cancer prophylaxis 90% tumors are related to influencing of external factors, and 10% - depend on genetic factors.

Neoplasia new growth & new


growth is called a neoplasm.

Neoplasia is new tissue growth that is: unregulated, these features irreversible, distinguish it from hyperplasia and repair monoclonal.
Monoclonal means that the neoplastic cells are derived from a single mother cell.

Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells. [Nowells Law]

Oncology (Greek oncos = tumor) is the study of tumors or neoplasms. Cancer is the common term for all malignant tumors. Although the ancient origins of this term are somewhat uncertain, it probably derives from the Latin for crab, cancerpresumably because a cancer "adheres to any part that it seizes upon in an obstinate manner like the crab."

Believe it or not, cancer has affected people for several centuries. It is not a new disease.

The word cancer came from the father of medicine, Hippocrates, a Greek physician. He used the Greek words, carcinos and carcinoma to describe tumors, thus calling cancer karkinos.

Hippocrates (460-377 BC) coined the term karkinos for cancer of the breast. The word cancer means crab, thus reflecting the true character of cancer since it sticks to the part stubbornly like a crab. He was certainly not the first to discover the disease.
The history of cancer actually begins much earlier.
The History of Cancer, Lisa Fayed, About.com July,2008

The world's oldest documented case of cancer hails from ancient Egypt, in 3000 b.c. The details were recorded on a papyrus, documenting 8 cases of tumors occurring on the breast. It was treated by cauterization. It was also recorded that there was no treatment for the disease, only palliative treatment. There is evidence that the ancient Egyptians were able to tell the difference between malignant and benign tumors. In ancient Egypt, it was believed cancer was caused by the Gods.
The History of Cancer, Lisa Fayed, About.com July,2008

Ancient Egyptian medical instruments depicted in a Ptolemaic period inscription on the Temple of Kom Ombo.

Ebers Papyrus treatment for cancer: recounting a "tumor against the god Xenus", it recommends "do nothing there against"
http://en.wikipedia.org/wiki/Ancient_Egyptian_medicine

Terminology
Hyperplasia - increase in the number of cells, Hypertrophy - increase in the sizes of individual cells. Atrophy is an adaptive response in which there is a decrease in the size and function of cells. Anaplasia - lack of differentiation.

Metaplasia : Transformation of a certain type of differentiated tissue into another type of differentiated tissue. Heteroplasia : Occurrence of non-neoplastic tissue at a location where it does not normally occur, either in a heterotopia or as a result of tissue dissemination.

All tumors, benign as well as malignant, have 2 basic components:


Parenchyma comprised by proliferating tumor cells; parenchyma determines the nature and evolution of the tumor. Supportive stroma composed of fibrous connective tissue and blood vessels; it provides the framework on which the parenchymal tumor cells grow.

NOMENCLATURE
Benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule.
For example, a benign tumor arising from fibroblastic cells is called a fibroma, a cartilaginous tumor is a chondroma, a tumor of osteoblasts is an osteoma.

Malignant tumours of epithelial origin are called carcinomas, while malignant mesenchymal tumours are named sarcomas (sarcos = fleshy)
For example, fibrosarcoma, liposarcoma, leiomyosarcoma for smooth muscle cancer, and rhabdomyosarcoma for a cancer that differentiates toward striated muscle).

Adenoma is the term applied to a benign epithelial neoplasm that forms glandular patterns as well as to tumors derived from glands but not necessarily reproducing glandular patterns. Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as papillomas

However, some cancers are composed of highly undifferentiated cells and are referred to as undifferentiated malignant tumours. Teratomas (can be benign), in contrast, are made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three.

"Knapsack tumor: lipoma Pleural sarcomatosis: metastatic sarcoma of the uterus

CANCER CELLS AND NORMAL CELLS


CANCER CELLS
Frequent mitoses Normal cell Nucleus

NORMAL CELLS

Blood vessel

Few mitoses

Abnormal heterogeneous cells

Loss of contact inhibition

Oncogene expression is rare Intermittent or co-ordinated growth factor secretion Presence of tumor suppressor genes

Increase in growth factor secretion


Increase in oncogene expression Loss of tumor suppressor genes

Characteristics of Benign and Malignant Neoplasms


Characteristics
Cell characteristics

Benign
Well-differentiated cells that resemble normal cells of the tissue from which the tumor originated

Malignant
Cells are undifferentiated and often bear little resemblance to the normal cells of the tissue from which they arose

Mode of growth

Tumor grows by expansion and does Grows at the periphery and sends out not infiltrate the surrounding tissues; processes that infiltrate and destroy the usually encapsulated by a fibrous capsule (exception uterine leiomyomas do surrounding tissues
not have fibrous tissue capsule)

Rate of growth

Rate of growth usually is slow

Rate of growth is variable and depends on level of differentiation; the more anaplastic the tumor, the more rapid the rate of growth Gains access to the blood and lymph channels and metastasizes to other areas of the body

Metastasis

Does not spread by metastasis

General effects

Tissue destruction Ability to cause

Usually is a localized phenomenon that does not cause generalized effects Often causes generalized effects such as unless its location interferes with vital anemia, weakness, and weight loss functions Often causes extensive tissue damage as the Usually does not cause tissue damage tumor outgrows its blood supply or unless its location interferes with blood encroaches on blood flow to the area; also may flow produce substances that cause cell damage Usually does not cause death unless its Usually causes death unless growth can be

Principal Pathways of Malignancy


1. Proliferation 2. Cell-Cycle Progression 3. DNA Repair 4. Immortalization 5. Apoptosis 6. Angiogenesis 7. Metastasis and Invasion

1. Age > 55 years - more than 75% of cancers. 2. Causes: 1)External factors: tobacco, 2) Internal factors: hormones,
alcohol, chemicals, radiation, pathogens immune conditions, inheriled mutations

3. Blacks a. Greatest risk for cancer and cancer-related deaths of any other racial group or ethnicity b. Applies to almost all cancers except malignant melanoma

4. Hispanics and Asians


Lower incidence rates for all cancers combined than whites b. Exceptions are for cancers associated with infections cervix (human papillomavirus), liver (hepatitis B and C), stomach (Helicobacter pylori)

5. Native Americans Highest incidence and


cancer-related deaths due to kidney cancer than all racial and ethnic populations.

Cancer incidence
1. Cancers in children a. Second most common cause of death in children (accidents most common cause) b. Acute lymphoblastic leukemia (-33%), central nervous system (CNS) tumors (-21%), neuroblastoma (~7%), Wilms' tumor (-5%). These are not common tumors in adults. 2. Cancers in men (in decreasing order) Prostate, lung, colorectal 3. Cancers in women (in decreasing order) Breast, lung, colorectal

1. Worldwide Malignant melanoma is increasing at the most rapid rate of all cancers. 2. China Nasopharyngeal carcinoma secondary to Epstein-Barr virus (EBV) 3. Japan Stomach adenocarcinoma due t0 smoked foods Epidemiology of Endometrial Cancer 4. Southeast Asia Hepatocellular carcinoma 5. Africa due to hepatitis B virus plus Burkitt's lymphoma due to EBV and Kaposi's sarcoma due t0 human aflatoxins (produced by herpes virus 8. Aspergillus) in food

Cancer Geography

Causal Tumorigenesis

Cancer is a genetic disorder that arises from a single body cell (monoclonal disorder). In humans and other animals, it may be triggered by noxious chemical, viral, and physical agents with mutagenic effects. Cells acquire several characteristics during the course of this disease.

CARCINOGEN METABOLISM
Three Main Categories:
I. Chemical Carcinogens II. Physical Carcinogens III. Viral Agents Carcinogens Environmental factors Mutations Cancer

Occupation related causes Lifestyle related causes


Tobacco Diet Sexual practices

Multifactorial causes Chemical carcinogens Ionizing radiation Viral carcinogens

CARCINOGENS

CHEMICAL CARCINOGENESIS
Direct-acting Carcinogens
A. Alkylating agents Anti-cancer drugs: cyclophosphamide
(transitional cell carcinoma of urinary bladder),

Promoters
saccharine & cyclamates Estrogen (endometrial carcinoma.

chlorambucil, busulfan, melphalan, nitrosourea etc. -propiolactone; Epoxides B. Acylating agents: Acetyl imidazole Dimethyl carbamyl chloride

Adenocarcinoma of the vagina is seen with increased frequency in adolescent daughters of mothers who had received estrogen therapy during pregnancy).

Anabolic steroids ( the risk of

developing benign and malignant tumors of the liver)

Contraceptive hormones ( the risk of

developing breast cancer. For long durations are benign tumors of the liver, and a few patients have been reported to have developed hepatocellular carcinoma.

Gregg Valentino

Procarcinogens
1. Polyclic, aromatic hydrocarbons (in tobacco, smoke, fossil fuel, soot, tar, minerals oil, smoked animal foods, industrial and atmospheric pollutants)
(Lung cancer, skin cancer, cancer of upper aerodigestive tract) Anthracenes (benza-, dibenza-, dimethyl benza-)
3,4-benzopyrene

Benzapyrene; Methylcholanthrene 2. Aromatic amines and azo-dyes: -naphthylamine; Benzidine (Bladder cancer) Azo-dyes (e.g. butter yellow, scarlet red) (hepatocellular carcinoma) 3. Naturally-occurring products Aflatoxin B1 (Hepatocellular carcinoma in association with hepatitis B virus) Actinomycin D; Mitomycin C; Safrole; Betel nuts 4. Miscellaneous This lady chews betel nuts the fruit of a palm Nitrosamine & Amides Asbestos (Bronchogenic carcinoma, pleural mesothelioma) Vinyl chloride (Angiosarcoma, liver) Chromium, nickel, other metals (Bronchogenic carcinoma) Arsenic (Squamous cell carcinoma of skin, lung cancer, liver angiosarcoma)

Stages: Initiation - primary exposure

Promotion - transformation

Progression - Cancer growth

Cancer

Initiation

normal cells are exposed to a carcinogen not enough to cause malignant transformation requires one round of cell division normal cells are exposed to a carcinogen
1. Direct-acting carcinogens 2. Indirect-acting carcinogens Cytochrome P450

Procarcinogen

Ultimate carcinogen

Promotion

initiated cells are exposed to promoters promoters are not carcinogens !


properties of promoters

reversible dose-dependent time-dependent

Physical Carcinogenesis
1. Radiation 1). Ionizing radiation-induced cancers a. Mechanism: PRE-IRRADIATION POST-IRRADIATION Hydroxyl free radical injury to DNA b. Examples (1) Acute myelogenous or chronic myelogenous leukemia ( risk of leukemia in radiologists and individuals exposed to radiation in nuclear reactors); (2) Papillary thyroid carcinoma (3) Lung, breast, and bone cancers (4) Liver angiosarcoma (Due to radioactive thorium Chondrosarcoma dioxide used to visualize the arterial tree) 2). UV light-induced cancers a. Mechanism Formation of pyrimidine dimers, which distort DNA b. Basal cell carcinoma, squamous cell carcinoma, malignant melanoma 2. Physical injury 1). Squamous cell carcinoma may develop in thirddegree burn scars. 2). Squamous cell carcinoma may develop at the orifices of chronically draining; sinuses (e.g., chronic osteomyelitis),

Ultraviolet Rays
UV-A = 320 - 400 nm UV-B = 280 - 320 nm UV-C = 200 - 280 nm
UV-C filtered by ozone

UV-B
Inhibition of cell division inactivation of enzymes induction of mutations cell death at high doses Squamous cell cancer Basal cell cancer Melanocarcinoma

Viral Carcinogenesis
Virus HCV HTLV-1 (human T-cell lymphotropic virus) MECHANISM RNA Viruses Produces postnecrotic cirrhosis Activates TAX gene, stimulates polyclonal T-cell proliferation, inhibits TP53 suppressor gene DNA Viruses Promotes polyclonal B-cell proliferation, which increases risk for t(8:14) translocation Activates proto-oncogenes, inactivates TP53 suppressor gene Acts via cytokines released from HIV and HSV Type 16 (-50% of cancers); E6 gene product inhibits; TP53 suppressor gene Type 18 (-10% of cancers); E7 gene product inhibits; RB suppressor gene ASSOCIATED CANCER Hepatocellular carcinoma T-cell leukemia and lymphoma

EBV (EpsteinBarr virus) HBV (hepatitis B virus) HHV-8 (human herpesvirus) HPV types 16 and 18, 31, 33 (human papillomavirus)

Burkitt's lymphoma, CNS lymphoma in AIDS, mixed cellularity Hodgkin's lymphoma, nasopharyngeal carcinoma Hepatocellular carcinoma

Kaposi's sarcoma in AIDS Squamous cell carcinoma of vulva, vagina, cervix, anus (associated with anal intercourse), larynx, oropharynx

Viruses (in brackets) in human tumours.

Viral carcinogenesis
Oral cancer Kaposi's sarcoma

Burkitt's lymphoma

Laryngeal papillomatosis

A, Replication: Step 1. The DNA virus invades the host cell. Step 2. Viral DNA is incorporated into the host nucleus and Tantigen is expressed immediately after infection. Step 3. Replication of viral DNA occurs and other components of virion are formed. The new virions are assembled in the cell nucleus. Step 4. The new virions are released, accompanied by host cell lysis. B, Integration: Steps 1 and 2 are similar as in replication. Step 3. Integration of viral genome into the host cell genome occurs which requires essential presence of functional T-antigen. Step 4. A transformed (neoplastic) cell is formed.

Step 1. The RNA virus invades the host cell. The viral envelope fuses with the plasma membrane of the host cell; viral RNA genome as well as reverse transcriptase are released into the cytosol. Step 2. Reverse transcriptase acts as template to synthesise single strand of matching viral DNA which is then copied to form complementary DNA resulting in double-stranded viral DNA (provirus). Step 3. The provirus is integrated into the host cell genome producing transformed host cell. Step 4. Integration of the provirus brings about replication of viral components which are then assembled and released by budding.

Lifestyle Risk Factors


Tobacco-related: Lung cancer Pancreatic cancer Bladder cancer Renal cancer Cervical cancer
Lung carcinoma in situ

Penetration of the vena cava: renal carcinoma

Diet-Related Risk Factors


Nitrates Salt Low vitamins A, C, E Low consumption of yellow-green vegetables

Gastric Cancer Esophageal Cancer

Diet-Related Risk Factors


High fat Low fiber Low calcium High fried foods

Colon Cancer Pancreatic Cancer Prostate Cancer Breast Cancer Uterine Cancer

Carcinoma of the prostate

Mycotoxins

Liver Cancer

Sexual Practices Risk Factors


Sexual promiscuity Multiple partners Unsafe Sex Human Papillomavirus

Cervical Cancer

Multifactorial Factors
Tobacco + Alcohol

Oral Cavity Cancer Esophageal Cancer

Tobacco + Asbestos Tobacco + mining Tobacco + uranium + radium

Respiratory Tract Cancer Lung Cancer

CHARACTERISTICS OF CANCER
Clonality Autonomy Anaplasia

Metastasis

CHARACTERISTICS OF CANCER

Clonality can be determined by glucose-6phosphate dehydrogenase (G6PD) enzyme isoforms. 1. Multiple isoforms (e.g., G6PDA, G6PDB, and G6PDC) exist; only one isoform is inherited from each parent. 2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome). 3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PDA, and 50% of cells have G6PDG). 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). 5. Only one isoform is present in neoplasia, which is monoclonal. 6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome.

Clonality

CHARACTERISTICS OF CANCER
Autonomy
Cancer cells are able to proliferate despite

regulatory influences. Unrestricted proliferation results in tumor formation. Mechanisms:

Growth factor secretion Increased number of cell receptors Independent activation of key biochemical process

Proliferation depends on the cell cycle.

A tumor usually is undetectable until it has doubled 30 times and contains more than 1 billion (10*9) cells. At this point, it is approximately 1 cm in size. After 35 doublings, the mass contains more than 1 trillion (10*12) cells, which is a sufficient number to kill the host.

The Hayflick limit is the number of times a normal human cell population will divide until cell division stops.

The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal human fetal cells in a cell culture will divide between 40 and 60 times. The population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis Carrel that normal cells are immortal. Hayflick found that cells go through three phases: The first is rapid, healthy cell division. In the second phase, mitosis slows. In the third stage, senescence, cells stop dividing entirely. Once a cell reaches the end of its life span, it undergoes a programmed cellular death called apoptosis. Each mitosis slightly shortens each of the telomeres on the DNA of the cells. Telomere shortening in humans eventually makes cell division impossible, and this aging of the cell population appears to correlate with the overall physical aging of the human body. This mechanism also appears to prevent genomic instability. Telomere shortening may also prevent the development of cancer in human aged cells by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility.

I) Epidermal growth factor (EGF) II) Fibroblast growth factor (FGF) III) Platelet-derived growth factor (PDGF) IV) Colony stimulating factor (CSF) V) Transforming growth factors- (TGF-) VI) Interleukins (IL) VII) Vascular endothelial growth factor (VEGF)

1) Proto-oncogenes are growth-promoting genes i.e. they encode for cell proliferation pathway. 2) Anti-oncogenes are growth-inhibiting or growth suppressor genes. 3) Apoptosis regulatory genes control the programmed cell death. 4) DNA repair genes are those normal genes which regulate the repair of DNA damage that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes.

1) Activation of growth-promoting oncogenes causing transformation of cell (mutant form of normal protooncogene in cancer is termed oncogene). Many of these cancer associated genes, oncogenes, were first discovered in viruses, and hence named as v-onc. Gene products of oncogenes are called oncoproteins. 2) Inactivation of cancer-suppressor genes (i.e. inactivation of anti-oncogenes) permitting the cellular proliferation of transformed cells. Anti-oncogenes are active in recessive form i.e. they are active only if both alleles are damaged. 3) Abnormal apoptosis regulatory genes which may act as oncogenes or antioncogenes. Accordingly, these genes may be active in dominant or recessive form. 4) Failure of DNA repair genes and thus inability to repair the DNA damage resulting in mutations.

MOLECULAR
Mutation

CARCINOGENESIS

the molecular hallmark of cancer

Gene Families in Cancer Development 1 - Oncogenes 2 - Tumor Suppressor genes

3 - Mutator genes

+ oncogenes

Oncogenes promote cell proliferation


dominant & highly conserved types: viral oncogenes [v-oncs] cellular oncogenes [c-oncs] Proto-oncogene Mutation Oncogene

Classification of Oncogenes A. Secreted Growth Factors


c-sis, hst

B. Cell Surface Receptors


erb B, fms, ret, trk, fes, fms

C. Intracellular Transducers
c-src, c-abl, mst, ras

Components of signal transduction pathways

D. DNA-binding Nuclear Proteins


myc, jun, fos

E. Regulators of the Cell Cycle


bcl, bax, bad

PROTOONCOGENE ABL

FUNCTION

MUTATION

CANCER

Chronic myelogenous Nonreceptor tyrosine Translocation t(9:22) leukemia (chromosome kinase activity 22 is Philadelphia chr.) Receptor synthesis Amplification Breast carcinoma (marker of aggressiveness)

HER (ERBB2)

MYC N-MYC RAS

Nuclear transcription Translocation t(8:14) Burkitt's lymphoma Nuclear transcription Amplification Guanosine triphosphate signal transduction Point mutation Neuroblastoma Leukemia; lung, colon, pancreatic carcinomas Multiple endocrine neoplasia lla/llb syndromes Osteogenic sarcoma, astrocytoma

RET SIS

Receptor synthesis
Growth factor synthesis

Point mulation Overexpression

Mechanisms of Oncogene Activation 1. Point Mutation


H-ras Normal Bladder ca [codon 12] CGC Gly CTC Val
H-ras GTP

2. Gene Amplification
Double minutes HSRs

Perpetual cell division

Normal copy

Multiple copies

Mechanisms of Oncogene Activation 3. Gene Translocation Ex. Chronic Myelogenous Leukemia [CML]

Mechanisms of Oncogene Activation 4. Viral Gene Integration


promoter

Viral promoter

ONCOGENS
Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators

Mechanisms of activation of protooncogenes to form growth promoting oncogenes.

Tumor Suppressor Genes


Synonym: anti-oncogenes Definition: Collective term for genes whose products physiologically inhibit cell proliferation, promote cell differentiation, and also suppress certain steps in tumorogenesis and metastasis. A. Regulate cell growth and, hence, decrease ("suppress") the risk of tumor formation; p53 and Rb (retinoblastoma) are classic examples. B. p53 regulates progression of the cell cycle from G1 to S phase, 1. In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes. 2. If DNA repair is not possible, p53 induces apoptosis. a). p53 upregulates BAX, which disrupts Bcl2. b). Cytochrome c leaks from the mitochondria activating apoptosis, 3. Both copies of the p53 gene must be knocked out for tumor formation (Knudson two-hit hypothesis). a). Loss is seen in > 50% of cancers. b). Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas.

TUMOR SUPPRESSOR GENE FAMILY


Retinoblastoma gene [RB1 gene] rare form of childhood malignancy

forms: hereditary & sporadic

pRb

location: 17p13.1 105-KDa nuclear protein

function: induces DNA repair or apoptosis; inhibits E2F [prevents G1 S transition]


inhibited by: phosphorylation, viral oncoproteins [E1A, E1B, HPV E6, E7] mutation: point mutation > deletion results to: loss of function & extended lifespan of p53 Clinical conditions: carcinomas, Li Fraumeni Syndrome

Cell Cycle Regulation


Process assures that cell accurately duplicates its contents. Important checkpoints are present at G1 and G2 and are regulated by protein kinases called cyclins (cdk).

Checkpoints determine whether the cell proceeds to next phase of the cycle.

The role of p53 in maintaining the integrity of the genome.


Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell-cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclindependent kinase inhibitor p21, and the GADD45 genes, respectively. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53-induced activation of the BAX gene promotes apoptosis. In cells with loss or mutations of p53, DNA damage does not induce cell-cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.

SOME TUMOR SUPPRESSOR GENES, THEIR FUNCTIONS, AND ASSOCIATED CANCERS


GENE APC (adenomatous
polyposis coli)

FUNCTION Prevents nuclear transcriplion (degrades catenin, an activator of nuclear transcription)

ASSOCIATED CANCERS

Familial polyposis (colorectal carcinoma)


Breast, ovary, prostate carcinomas Relinoblastoma, osteogenic sarcoma, breast carcinoma Pancreatic and colorectal carcinomas

BRCA1/BRCA2 Regulates DNA repair (breast cancer)

RB
(retinoblastoma)

Inhibits G1 to S phase Inhibits G, to S phase

TGF-
(transforming growth factor-)

Inhibits G1 to S phase. Repairs Lung, colon, breast carcinomas. LiTP53 DNA, activates BAX gene (initiates Fraumeni syndrome: breast carcinoma, apoptosis) brain tumors, leukemia, sarcomas Von Hippel-Lindau syndrome: cerebellar hemangioblasloma, retinal angioma, renal VHL (Von Regulates nuclear transcription Hippel-Lindau ) cell carcinoma (bilateral), pheochromocytoma (bilateral) WT1 (Wilms' Regulates nuclear transcription Wilms' tumor
tumor)

Antiapoptosis genes; BcL2 family of genes Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g., Bcl2) a. Protein products prevent cytochrome c from leaving mitochondria. Cytochrome c in the cytosol activates caspases initiating apoptosis. b. Mutation causes increased gene activity (e.g., overexpression), which prevents apoptosis; e.g.. B-cell follicular lymphoma. (1) BcL2 gene family (chromosome 18) produces gene products that prevent mitochondrial leakage of cytochrome c (signal for apoptosis). (2) Translocation t(14; 18) causes overexpression of the BcL2 protein product. Prevents apoptosis of B lymphocytes causing B-cell follicular lymphoma Apoptosis genes a. Regulate programmed cell death (ex. BAX apoptosis gene) (1) Activated by a TP53 suppressor gene product if DNA damage is excessive (2) BAX protein product inactivates the BcL2 antiapoptosis gene. (3) Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative, which prevents apoptosis.

Anaplasia
The third characteristic feature of tumor cells is anaplasia, which is cells structural and biochemical organization simplification, coming back to embryonic state. Neoplastic cells lose a capacity for differentiation and can not form the specific tissue complexes. Tumor arises from one mutational maternal cell. However such cells differ from their general ancestor by much parameters. These distinctions consearn the cell structure, its organelles, metabolism, specific properties and functions. Therefore the following kinds of anaplasia are distinguished: morphological, biochemical, physical and chemical, functional, immunological.

The

essence of morphological anaplasia is in appearance of atypic cultural and tissue. Description of cultural atypic lays in: cellular polymorphism, nuclear size increase, polynuclear state, nuclear hyperchromatosis, nucleoluses amount increase, mitochondrias changes Conjunctival melanoma quantative size decrease, crests disappearance Tissue atypism is sizes and shapes of tissue structures change, sometimes is the total loss of morphological tissue signs.

Biochemical anaplasia is the tumor cells metabolism peculiarities. Its are arose their genetic system changes, enzymic spectrum of such cells gets changed. All cells get alike by enzymic admission (unification of isoenzymic spectrum). The most typical biochemical feature of neoplastic cells concern proteins and carbohydrates metabolism. Proteins metabolism peculiarities are:

synthesis activation of nucleic acids, DNA-polymerase inactivation, increase of proteins synthesis, decrease of proteins disintegration.

anaerobic glycolysis activation, aerobic glycolysis presence, oppression of Krebs cycle by powerful glycolytical enzymes system.

Carbohydrates metabolism and energetic of tumor cells is also differ of norm. The main energy sources in normal cells are anaerobic and aerobic carbohydrates disintegration, that is glycolysis and Krebs cycle. Neoplastic cell also receives the energy owing to glycolysis and Krebs cycle. However glycolysis role in tumor cell is more, than in normal one. The tumor cells energetic supply include:

Functional anaplasia displays in loss or perversion of tumor cells function. For example, in neoplastic thyroid cells a surplus amount of hormones thyroxine and triiodothyronine can be synthesized, thyrotoxicosis arises. In other cases separate functions of tumor cells fall out, for example, bilirubin does not get conjugated in hepatome. In very malignant neoplastic cells functions are totally lost. Sometimes such cells begin doing the functions, which are not specific for them (bronchus cancer synthesizes the gastrointestinal hormones).

Immunological anaplasia is change of tumor cell antigen properties. In such cells antigen admission is changed. Several deviation kinds of antigen out of norm admission are distinguished antigen simplification, antigen divergence and antigen reversion. Antigen simplification is the general number of neoplastic cells antigens diminution. For example, the cells of normal tissue synthesize up to 7 typical antigens, while same tissue tumor cells synthesize only 2-3 antigens. The idea of antigen divergence is in the fact of neoplastic cells starting to synthesize heterologous antigens. For example, hepatoma (liver tumor) begins synthesizing organospecific spleenic antigens, or other organs antigens. Antigen reversion means neoplastic embryonic antigens synthesis. For example, human liver cancer synthesizes a special embryonic protein, which is a-fetoprotein.

Invasion and Metastasis


The defining characteristic of a malignancy. Invasion: active translocation of neoplastic cells across tissue barriers. Critical pathologic point: local invasion and neovascularization. These events may occur before clinical detection.

Metastasis
1. Benign tumors do not metastasize. 2. Malignant tumors metastasize. 3. Pathways of dissemination: a. Lymphatic spread to lymph nodes (usual mechanism of dissemination of carcinomas) b. Hematogenous spread: 1) Usual mechanism of dissemination for sarcomas 2) Cells entering the portal vein metastasize to the liver. 3) Cells entering the vena cava metastasize to the lungs.

Metastasing
The final progression stage of any tumor is its transformation into the malignant neoplasm. The major criteria of malignant tumor is its ability to generalisation, that is to metastasing. Metastasing includes three stage: neoplastic invasion into the surrounding tissues, tumor cells transport with the blood and lymphatic vessles, their implantation in different organs and tissues. Separate cells evacuation out of the neoplastic node takes place in case of intercellular contacts relaxation. Tumor loses calcium, which must turn intercellular spaces cementated in malignisation process. Diminished amount of desmosomes, which create the intercellular contacts arises in pernicious neoplasms. The amount of gangliosides is disranked on the cellular surface of malignant tumor.

ATTRIBUTES OF CANCER Metastasis

Two basic steps:

Destruction of the BM Attachment to the laminin of distant BM

Genes up-regulated among good metastasizers:


EDGF receptor Basic Fibroblast Growth Factor Type IV Collagenase -Cathepsin (under-expressed) Cathepsin B (a lamininase) Heparanase

STAGING OF CANCER A. Assessment of size and spread of a cancer B. Key prognostic factor; more important than grade C. Determined after final surgical resection of the tumor D. Utilizes TNM staging system 1. Ttumor (size and/or depth of invasion) 2. Nspread to regional lymph nodes; second most important prognostic factor 3. Mmetastasis; single most important prognostic factor

Tissue destruction: carcinoma of the maxillary sinus

Metastasis: cervical lymph node

Cancer "crater: liver metastases

Lymph node metastasis

ANGIOGENESIS
Formation of new blood vessels from existing vascular bed Carried out by endothelial cells (EC) and extra cellular matrix (ECM) Regulated by angiogenic factors (inducers and inhibitors) * A tumor is unable to grow larger than 1 mm3 w/o developing a new blood supply

Components of Angiogenesis
1)

ENDOTHELIAL CELLS Fenestrated Increased cell adhesion molecules (Eselectin) Increased integrins 3 essential for viability during growth Activated ECs release: bFGF PDGF IGF-1

Components of Angiogenesis
2) INDUCERS OF ANGIOGENESIS

VEGF main inducer TGF- TNF- low concentration - inducer high concentration - inhibitor PDGF/thymidine phosphorylase TGF- EGF IL-8

Components of Angiogenesis
3) CELL ADHESION MOLECULES (CAM) Mediate cell-cell adhesion processes Selectins IG Supergene family- ICAM, VCAM Cadherins Integrins- vitronectin receptor 4) PROTEASES Degrade ECM to provide suitable environment for EC migration thru adjacent stroma Ex: Metalloproteinases (MMP)

Components of Angiogenesis
5) ANGIOGENESIS INHIBITORS Interferon TSP-1 Angiostatin Endostatin Vasostatin CLINICAL SIGNIFICANCE: Tumor angiogenesis switch is triggered as a result of shift in the balance of stimulators to inhibitors

Tumor cells are heterologous for the organism. They synthesizethe proteins, which are not character for normal cells. Neoplasms product specific swelling antigen. Their specificity is conventional, but it is still sufficient for immune reaction development. A final result depends on immune attack intensity greatly: that means, if the transformed cell is going to reproduct or not; is the tumor going to arise, or not. Neoplasms are observed in people with congenital immunodeficiency 10000 times more often, than in persons with normal immune system. The malignant neoplasms arise in patients, with transplanted organ (for example, kidney) very often. Immunodepressive drugs are being prescribed with the purpose of transplanted organ rejection prophylaxy in such patients. Tumors in are observed in such cases 100 times more frequent, than in the rest of population. These facts testify, that the transformed cells underlie the organism immune system supervision. In most people they eliminate in time. A transformed cell exists, reproducts, and produces the neoplasm in a fact of immune supervision insolvency. Tumor renders an oppressive action upon the organism immune system in its own way. Immunodepression gets developed. The matters, which render immunodepressive action are produced in neoplastic cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryonic antigens (a-fetoprotein), glucocorticoids belong to them. -suppressors activity in patients with tumors is increased. They slow down antineoplastic immunity. One more reason of immunodepression in oncologic patients is the disparity between neoplastic growth speed and immune answer development speed. Lymphoid cells reproduct slower, than tumor cells do. Adequate immune answer is late.

Immune system and neoplastic growth

Systemic neoplastic action upon the organism


Tumor is not locally isolated process. It renders an influence upon the diverse organism functions. This is concerning the malignant neoplasms especially. Their systemic action displays the cancer cachexy. There are a few components of its development. Tumor absorbs the glucose reinforcely. Chronic hypoglycaemia tendency arises. Glycogen disintegrates in liver and muscles reinforcely. Glyconeogenesis gets increased. However, this compensatory mechanism has the negative characteristics. Firstly, glucocorticoids cause the albumens disintegration of immunocompetence organs (thymus, spleen, lymphoid tissue of other organs). Secondly, of big amount of amino acids in glyconeogenesis usage gets the organic albumens synthesis limited. Diverse organs dystrophy develops, muscles first of all. Neoplastic growth can be described with the intensive synthetic processes. Plastic material (amino acids, nucleic acids) is very important for this. Neoplasm absorbs these matters not only nutritional, but from other organs also. It is named as nitrogen snare. all of other tissues are having amino acid deficiency. They can not synthesize their own proteins in a necessary volume. This is one more link of cancer cachexy pathogens.

Neoplastic Tumors

Tumor Complications
The lesions described below complicate the simple growth of the tumor. The combination of such lesions with tumor expansion and metastasis constitute neoplastic disease that extends beyond the tumor as such. Local Complications Stenosis: Tumors can lead to several compression syndromes. Expansion of the tumor compresses the A surrounding tissue (A1) and causes stenosis in hollow organs (A2), compression of the small bowel by a mesenterial liposarcoma; Complications may include difficulties in swallowing, impaired micturition, disruption of intestinal motility, and also increased intracranial pressure. Infiltration of the tumor can cause congestion in a hollow organ. Complications may include prestenotic dilation of the duct, stasis and congestion of secretions or excretions, and bacterial infestation of the congested area.

2
Tumor compression (mesenterial liposarcoma)

Budd-Chiari Syndrome

Tumor Complications
Circulatory Disruption: Tumor growth that compromises or infiltrates vascular structures produces a variety of lesions. Obstruction of venous drainage is common and successively leads to varicose changes in the walls of the veins and thrombosis. Vascular thrombosis may result from vascular stenosis and/or substances produced by the tumor itself that promote coagulation.

Bleeding due to erosion of vascular structures may lead to spitting of blood from the lungs or bronchi (hemoptysis), vomiting of blood (hematemesis), passage of bloody stools (melena), blood in the urine (hematuria), acyclic bleeding from the uterus (metrorrhagia), and hemorrhagic effusions (B).
B
Hemorrhagic effusion (lung cancer)

Tumor Necrosis (C): occurs as a result of the interplay of Necrosis: uterine sarcoma several factors. These include: Thrombotic arterial obstruction; Vascular compression by the tumor; Twisting of the tumor pedicle; Cytokines (macrophagic TNF-a); Aggressive tumor therapy. Complications of tumor necrosis: C Ulceration of the inner or outer body surface may occur, primarily in gastrointestinal, skin, and breast Skin ulceration: cancer (D). breast cancer Perforation of the tumor necrosis may occur into hollow organs or through the surface of the skin (E). Fistulas may form that communicate with adjacent organs. Disruption of Organ Function: occurs especially in tumors that not only mechanically alter the organ D parenchyma and its supporting tissue but also destroy them. Perforation of the cheek: Particularly susceptible tissues include: cancer of the tongue Bone destruction: Neurovascular structures; Ewing sarcoma Urinary tract, Intestinal tract; Skeletal system, where bone tumors can cause pathologic fractures (F). F E

Systemic Complications
Advanced neoplastic disease regularly produces four types of systemic lesions.

Tumor Metastases: occasionally occur even in the early phases of neoplastic disease. Cancer Cachexia: involves weight loss in cancer patients. Causes include: Impaired swallowing due to the tumor; Impaired digestion due to the tumor; Generation of TNF-a by macrophages stimulated by tumor-associated antigens. Generation of leptin (fat-cell hormone). This results in loss of appetite (anorexia), reduced intake of nutrients, decreased body fat, and increased energy consumption. Tumor Anemia: produces the characteristic pale skin of cancer patients. It is due to several factors, including: Blood loss due to internal bleeding; Lack of substances that promote maturation of blood cells; Autoreactive antibodies against erythrocytes; Displacement of bone marrow by tumorous infiltrates.

Paraneoplastic Syndromes
Definition: Collective term for a group of generalized pathologic manifestations that are not attributable to the local effects of a tumor but are linked to the existence of a tumor and can regress after the tumor has been removed. Pathogenesis: Often unclear. Cell destruction occurs due to formation of autoreactive antibodies against tumor antigens and self antigens and as a result of apoptosis caused by certain tumor proteins. Dysfunction results from synthesis of peptides with endocrine and enzymatic effects. Endocrinopathies General pathogenesis: Tumors synthesize ectopic hormones of substances similar to hormones. The most important forms are as follows: Cushings syndrome is caused by formation of ACTH and occurs in patients with bronchial cancer. Flushs syndrome is caused by formation of serotonin and leads to facial erythema, diarrhea, colic, and bronchospasm. It occurs in patients with bronchial or ileal carcinoid. Schwartz-Bartters syndrome is caused by formation of proteins resembling ADH and leads to hyponatremia. It occurs in patients with small cell bronchogenic carcinoma. Hypercalcemia syndrome is caused by formation of parathormone-like protein. It occurs in patients with squamous cell bronchogenic carcinoma or renal cell carcinomas.

PARANEOPUSTIC SYNDROMES
SYNDROME ASSOCIATED CANCER COMMENT Black, verrucoid-appearing lesion Myaslhenia gravis-like symptoms(e.g., muscle weakness); antibody directed against calcium channel Periosteal reaction of distal phalanx (often associated with clubbing of nail) Acanthosis nigricans Stomach carcinoma Eaton-Lambert syndrome Small cell carcinoma of lung

Hypertrophic osteoarthropathy Nonbacterial thrombotic endocarditis

Bronchogenic carcinoma

Mucus-secreting pancreatic Sterile vegetations on mitral valve and colorectal carcinomas Sudden appearance of numerouspigmenled seborrheic keratoses (Lescr-Trdlat sign) Release of procoagulants (Trousseau's sign) Diffuse membranous glomerulopathy

Seborrheic keratosis Stomach carcinoma Superficial migratory Pancreatic carcinoma thrombophlebitis Lung, breast, stomach Nephrotic syndrome carcinomas

DISORDER Cushing syndrome

ASSOCIATED CANCER Small cell carcinoma of lung, medullary carcinoma of thyroid

ECTOPIC HORMONE ACTH (adrenocorticotropic hormone) hCG (human chorionic gonadotropin) PTH-relaled protein (parathyroid hormone) Calcitriol (vilamin D) Calcitonin Insulin-like factor Antidiuretic hormone Erythropoietin

Gynecomastia

Choriocarcinoma (testis)
Renal cell carcinoma, primary squamous cell carcinoma of lung, breast carcinoma. Malignant lymphomas (contain 1-hydroxylase) Medullary carcinoma of thyroid Hepatocellular carcinoma Small cell carcinoma of lung Renal cell and hepatocellular carcinomas

Hypercalcemia

Hypocalcemia Hypoglycemia Hyponatremia Secondary polycythemia

Nerve and Muscle Syndromes Pathogenesis: Nerve cells and/or muscle fibers are destroyed by autoimmune processes and by tumor-induced apoptosis. The most important forms are as follows: Myasthenia gravis occurs in patients with thymus tumors (thymomas). Limbic encephalopathy occurs in patients with small cell bronchogenic carcinoma. Degeneration of the cerebellar cortex occurs in patients with small cell bronchogenic carcinoma, breast cancer, or ovarian carcinoma. Vascular and Hematologic Changes Hemolysis: The tumor synthesizes cytotoxic substances and/or autoreactive antibodies, damaging the bone marrow and leading to hemolytic anemia. This occurs in patients with leukemias or Hodgkins diseases lymphoma. Erythrocyte proliferation: The tumor synthesizes substances that stimulate erythropoiesis (erythropoietin), leading to polyglobulism (an overabundance of erythrocytes). This occurs in patients with renal cell carcinoma. Leukocyte proliferation: The tumor synthesizes substances that stimulate myelopoiesis, leading to a leukemoid reaction. This occurs in patients with stomach cancer or large cell bronchogenic carcinoma. Macroscopic coagulopathy: The tumor synthesizes thromboplastic substances that lead to thrombosis. This occurs in patients with pancreatic or adenoid carcinomas. Disseminated intravascular coagulation: The tumor synthesizes thromboplastic and fibrinolytic substances that consume the clotting factors. This occurs in patients with leukemias. Note: Coagulopathy is characterized by thrombotic vascular occlusion (primarily in the lung), whereas disseminated intravascular coagulation is characterized by hyalin microthrombi (primarily in the microvasculature of the lung).

Dermatologic Disorders Acanthosis nigricans manifests itself as thickening of the skin with clearly discernible papillary lines, hyperpigmentation, and wart-like papillomas. It occurs in patients with stomach cancer or squamous cell bronchogenic carcinoma. () Bazexs syndrome (paraneoplastic acrokeratosis) manifests itself as reddish purple plaques of calcification on the hands, feet, nose, and ears. It occurs in patients with carcinoma of the tongue or tonsils. (B) Erythema gyratum repens is a rare skin rash resembling zebra stripes that changes daily. It occurs in patients with various carcinomas. (C, D) Hypertrichosis lanuginosa is a rare manifestation involving excessive growth of the head and body hair. It occurs in E patients with various carcinomas. (, F) B D

7 warning signs of cancer


C A U T I O N change in bowel or bladder habit a sore that doesnt heal unusual bleeding or discharge thickening or lump indigestion obvious change in wart or mole nagging cough or hoarseness

Literature
Handbook of general and Clinical Pathophysiology/ Edited by prof.A.V.Kubyshkin, CSMU, 2005. p. 130-138 Pathophysiology/ Edited by prof.Zaporozan, OSMU, 2005 p.105-114 General and clinical pathophysiology/ Edited by Anatoliy V. Kubyshkin Vinnytsia: Nova Knuha Publishers 2011. p. 166-183 Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine Publishing, 2010, p. 142-160. General and clinical pathophysiology. Workbook for medical students and practitioners. Odessa. 2001. J.B.Walter I.C.Talbot General pathology. Seventh edition. 1996. Stephen J. McPhee, William F. Ganong. Pathophysiology of Disease, 5th edition. 2006. Robbins and Cotran Pathologic Basis of Disease 7th edition / Kumar, Abbas, Fauto 2006. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin.- New York, Milwaukee- 2009 p 156-197.

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