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Dr. Nazar Jawhar

Biology of tumor growth

Dr. Nazar Jawhar

Tumor angiogensis:
Solid tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized. Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products Angiogenesis is a requisite for: Continued tumor growth through supplying nutrient & oxygen. Metastasis of tumor.

Dr. Nazar Jawhar

Cancer cells can stimulate neo-angiogenesis, during which new vessels sprout from previously existing capillaries. It is stimulated by angiogenic factors secreted by the tumor and by other attending cells as macrophages & lymphocytes. Example VEGF, Basic FGF, angiogenin. Recent reports have shown that nontoxic neutralizing monoclonal antibodies to angiogenin prevents the establishment of human tumor implants mice.

Dr. Nazar Jawhar

Invasion and metastasis are biologic hallmarks of malignant tumors. They are the major cause of cancer-related morbidity and mortality It can be divided into the following steps: 1) Loss of adherence i.e detachment of tumor cells from each other. ( normal cells are attached and glued to each other by transmembrane molecules e.g E-cadherin). In some cancer expression of E-cadherin is reduced resulting in loss of adhesion.
Mechanism of invasion & metastasis:

Dr. Nazar Jawhar

2) Invasion of the ECM: After loosening up, tumor cells gain motility and invade through the matrix. This is achieved by attachment of tumor cells to the ECM components through acquisition of receptors for these components (as integrin for basement membrane). Degradation of the ECM by release of digestive enzymes by tumor cells as metalloproteinase, cathepsin D and collagenase.

Dr. Nazar Jawhar

Dr. Nazar Jawhar
3) Migration of tumor cells through the ECM, promoted by cytokines. 4) Vascular dissemination and homing (intravasation). Within the circulation, tumor cells tend to aggregate in clumps. This is favored by adhesions of tumor cells to each other and to blood cells particularly platelets (CD11 is involved in this process. traveling, extravasation,..

Dr. Nazar Jawhar

Dr. Nazar Jawhar
Etiology of cancer
Cancer results from genetic damage which could be acquired or inherited. Acquired mutation may results from: Chemical agents Radiant energy Microbial agents

Dr. Nazar Jawhar

Chemical carcinogenesis:
The first man who unmasked the rule of chemicals in carcinogenesis was Sir Percival Pott more than 200years ago when he attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. Such chemicals are of extremely diverse structure & include both natural and synthetic products. Chemical carcinogenic agents are of 2 types:

Dr. Nazar Jawhar

A- Direct acting chemicals
These substances are active by themselves, they do not require metabolic conversion. They are weak carcinogens Examples: alkylating & acylating agents ( anticancer chemotherapy) as cyclophosphamide, chlorambucil, nitrosureas,.. They exerts their therapeutic effects by interacting and damaging DNA, this action also render them carcinogenic.


Dr. Nazar Jawhar
B- Indirect acting chemicals (Procarcinogens):
They require metabolic conversion inside the body. The largest group. Potent carcinogens.

Dr. Nazar Jawhar

Most of the known carcinogens are metabolized by cytochrome P-450-dependent mono-oxygenases. The genes that encode these enzymes are quite polymorphic, and the activity of these enzymes have been shown to vary among different individuals. Because these enzymes are essential for the activation of procarcinogens, the susceptibility to carcinogenesis is regulated in part by polymorphisms in the genes that encode these enzymes. Thus, it may be possible to assess cancer risk in a given individual by genetic analysis of such enzyme polymorphisms

Dr. Nazar Jawhar

Procarcinogens That Require Metabolic Activation
POLYCYCLIC AND HETEROCYCLIC AROMATIC HYDROCARBONS
Benz(a)anthracene Benzo(a)pyrene Dibenz(a, h)anthracene 3-Methylcholanthrene 7, 12-Dimethylbenz(a)anthracene
AROMATIC AMINES, AMIDES, AZO DYES
2-Naphthylamine (β-naphthylamine)Benzidine2-AcetylaminofluoreneDimethylaminoazobenzene (butter yellow) Natural Plant and Microbial Products
Aflatoxin B1 Cycasin Safrole Betel nuts
OTHERS
Nitrosamine and amides Vinyl chloride, nickel, chromium Insecticides, fungicides Polychlorinated biphenyls

Dr. Nazar Jawhar

POLYCYCLIC AND HETEROCYCLIC AROMATIC HYDROCARBONS
Benz(a)anthracene Benzo(a)pyrene Dibenz(a, h)anthracene 3-Methylcholanthrene 7, 12-Dimethylbenz(a)anthracene
- Very potent carcinogens. Can induce tumor in a wide variety of tissue as skin CA, sarcomas,… Produced in the combustion of tobacco, smooked meat and fish.


Dr. Nazar Jawhar
AROMATIC AMINES, AMIDES, AZO DYES
2-Naphthylamine (β-naphthylamine)Benzidine2-AcetylaminofluoreneDimethylaminoazobenzene (butter yellow) β-naphthylamine in rubber industry & azo dyes developed to color food. Carcinogenicity is exerted mainly in the liver except B-naphthylamine.

Dr. Nazar Jawhar

Natural Plant and Microbial Products
Aflatoxin B1 Cycasin Safrole Betel nuts
Aflatoxin produced by Aspergillus flavuis , thrive on improperly stored grains and peanuts. Results in hepatocellular carcinoma in Africa and Far East.

Dr. Nazar Jawhar

OTHERS
Nitrosamine and amides: Vinyl chloride, nickel, chromium Insecticides, fungicides Polychlorinated biphenyls
Nitrosamine and amides used as food preservative, results in CA stomach.

Dr. Nazar Jawhar

Typical Use or Occurrence
Human Cancer Site
Agents or
Byproduct of metal smelting; component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips
Lung, skin, hemangiosarcoma
Arsenic and arsenic compounds
Formerly used for many applications because of fire, heat, and friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing papers, and floor tiles
Lung, mesothelioma; gastrointestinal tract
Asbestos
Principal component of light oil; despite known risk, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents; formerly widely used as solvent and fumigant
Leukemia, Hodgkin lymphoma
Benzene
Missile fuel and space vehicles; hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors
Lung
Beryllium and beryllium compounds
Uses include yellow pigments and phosphors; found in solders; used in batteries and as alloy and in metal platings and coatings
Prostate
Cadmium and cadmium compounds
Component of metal alloys, paints, pigments, and preservatives
Lung
Chromium compounds
Nickel plating; component of ferrous alloys, ceramics, and batteries; by-product of stainless-steel arc welding
Nose, lung
Nickel compounds
From decay of minerals containing uranium; potentially serious hazard in quarries and underground mines
Lung
Radon and its decay products
Refrigerant; monomer for vinyl polymers; adhesive for plastics; formerly inert aerosol propellant in pressurized containers
Angiosarcoma, liver
Vinyl chloride

Dr. Nazar Jawhar

Mechanism of action of chemical carcinogens:
Because malignant transformation results from mutations, it should come as no surprise that most chemical carcinogens are mutagenic. Indeed, all direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA. Although any gene may be the target of chemical carcinogens, the commonly mutated oncogenes and tumor suppressors are important targets of chemical carcinogens, such as RAS and p53.

Dr. Nazar Jawhar

The process of chemical carcinogenesis can be divided into 2 stages: I- Initiation: Result from exposure to appropriate dose of carcinogens. All initiating chemical are highly reactive electrophiles (have electron-deficient atoms) that can react with nucleophilic (electron-rich) sites in the cell. Their targets are DNA & RNA, resulting in permanent DNA damage. It is irreversible. Initiation alone is not sufficient to produce CA

Dr. Nazar Jawhar

II- Promotion: Application of promoters induce CA in initiated cells. Not carcinogenic by themselves. Induce cellular proliferation so rendering the cells susceptible to additional mutation. Reversible. No DNA damage. Could be endogenous or exogenous (such as phorbol esters, hormones, phenols, and drugs)

Dr. Nazar Jawhar

Steps of chemical carcinogensis:

Dr. Nazar Jawhar

Radiation carcinogenesis
Three forms: UV Radiant energy Particulate radiation All can transform cells and induce CA. Examples.

Dr. Nazar Jawhar

Many individuals pioneering the use of x-rays developed skin cancers. Miners of radioactive elements (in Europe and United States have a tenfold increased incidence of lung cancers compared to the rest of the population. Most telling is the follow-up of survivors of the atomic bombs dropped on Hiroshima and Nagasaki. Initially there was a marked increase in the incidence of leukemias-principally acute and chronic myelogenous leukemia-after an average latent period of about 7 years.

Dr. Nazar Jawhar

Mechanism:
Ionizing radiation causes chromosome breakage, translocations, and, less frequently, point mutations, leading to genetic damage and carcinogenesis. UV rays induce the formation of pyrimidine dimers within DNA, leading to mutations

Dr. Nazar Jawhar

Ultraviolet Rays -UV
The UV portion of the solar spectrum can be divided into three wavelength ranges: UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm). Of these, UVB is believed to be responsible for the induction of cutaneous cancers. UVC, although a potent mutagen, is not considered significant because it is filtered out by the ozone shield around the earth (hence the concern about ozone depletion). Mostly responsible for skin CA as SCC, BCC, melanoma.

Dr. Nazar Jawhar

The degree of risk depends on the type of UV rays, the intensity of exposure, and the quantity of the light-absorbing "protective mantle" of melanin in the skin.

Dr. Nazar Jawhar

Ionizing radiation
X-ray, gamma rays,…Induce cancer in any part of the body but the most common radiation induced cancer are: Leukemias followed by thyroid cancer, followed by breast lung, and salivary glands.In contrast, skin, bone, and the gastrointestinal tract are relatively resistant to radiation-induced neoplasia

Dr. Nazar Jawhar

Viral and Microbial Oncogenesis
Many DNA and RNA viruses have proved to be oncogenic in animals as disparate as frogs and primates. Despite intense scrutiny, however, only a few viruses have been linked with human cancer.

Dr. Nazar Jawhar

Example HTLV-1 (RNA): T-cell leukemia/lymphoma in Japan. DNA viruses: as HPV e.g type 16,18,31 (cervical & oropharyn CA Epstein-Barr virus (EBV) Hepatitis B &C virus (HBV) Kaposi sarcoma herpes virus, also called human herpes virus 8 Merkel cell polyomavirus, has been identified in Merkel cell carcinomas

Dr. Nazar Jawhar

The oncogenic potential of HPV can be related to the products of two viral genes, E6 and E7. Together, they interact with a variety of growth-regulating proteins encoded by proto-oncogenes and tumor suppressor genes. The E7 protein binds to the RB protein while E6 protein binds to and mediates the degradation of p53. The primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of anti-HPV vaccines in preventing cervical cancer

Dr. Nazar Jawhar

EBV, a member of the herpes family, has been implicated in the pathogenesis of several human tumors: African form of Burkitt lymphoma B-cell lymphomas in immunosuppressed individuals A subset of Hodgkin lymphoma Nasopharyngeal and some gastric carcinomas It seems that EBV is not directly oncogenic, but by acting as a polyclonal B-cell mitogen, it sets the stage for the acquisition of the t(8;14) translocation and other mutations, which ultimately release the cells from normal growth regulation.

Dr. Nazar Jawhar

the oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation with hepatocyte death leading to regeneration and genomic damage.

Dr. Nazar Jawhar

H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. The scenario is similar to that of HBV- and HCV-induced liver cancer. It involves increased epithelial cell proliferation in a background of chronic inflammation

Dr. Nazar Jawhar

Host Defense against Tumors-Tumor Immunity Tumor antigen ANTITUMOR EFFECTOR MECHANISMS IMMUNE SURVEILLANCE AND ESCAPE




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