CHEMICALS AND CANCER

Toxicology

Cancer Cancer is a term used for diseases in which abnormal cells

divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems.

Tumor or tumour is the name for a swelling or lesion formed by an abnormal

growth of cells (termed neoplastic).Tumor is not synonymous with cancer. A tumor can be benign, pre-malignant,

malignant, whereas cancer is by definition malignant.

Neoplasm Neoplasm is an abnormal mass of tissue as a result of

neoplasia.

Benign tumor are not cancerous. They can often be removed, and, in

most cases, they do not come back. Cells in benign tumors do not spread to other parts of the body.

Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis.

Oncogenes

An oncogene is mutated form of proto-oncogene. Proto-oncogenes code for proteins that help to

regulate cellular growth and differentiation. Many abnormal cells normally undergo a programmed

form of death (apoptosis). Activated oncogenes can cause those cells to survive and proliferate. Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer.

RAS, WNT, MYC, ERK, TRK. HER2/neu Products of oncogenes (Growth factor, Receptors,

cytoplasmic kinases, Transcription factors, signal transduction)

Tumor suppressor gene

A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The gene codes for

Inducer of differentiation Cell adhesion molecules Inhibitor of cellular proliferation Transcription factors Inhibitors of angiogenesis BRCA1, APC, p53

p53

Associated with over 50% of human cancer. Coding of enzyme that are imp for DNA

repair, apoptosis and regulation of cell division.

p53 is guardian of genome. Mutated p53 gene can be inherited. The name p53 is in reference to its

apparent molecular mass:(53kDa). The p53 gene can also be damaged in cells

by mutagens (chemicals, radiation, or viruses).

p53 pathway

Characteristics of cancer cell

The malignant phenotype refers to

structural, functional and behavioral differences in the cells of malignant neoplasm.

Loss of contact growth inhibition Autonomy of proliferation Avoidance of apoptosis Aberrant differentiation Induction of angiogenesis

Characteristics of cancer cell

Tumor can be grade from 1 to 4 that

corresponds to its degree of malignancy. Microscopic view of malignant cell Large nucleus Prominent nucleoli Irregularities of chromosomes

Production of embryonic proteins (Alpha-fetoprotein and carcinoembryonic antigen).

Dysplasia "malformation", is a term used in pathology to refer to an abnormality of development.

Definitions

Metaplasia: (change in form) is the reversible replacement of one differentiated cell type with another mature differentiated cell type.

Anaplasia: Reversion of cells to an immature or a less differentiated form, as occurs in most malignant tumors.

Hyperplasia is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen.

Benign and Malignant tumors

Benign tumor can be life threatening (size, location) Adrenal gland, Islets of langerhans of the pancreas.

Carcinoma: epithelial tissue Sarcoma: connective tissue Blastoma: embryonic tissue Melanoma: cancer of melanocyte Leukemia: Sarcoma of blood forming tissue

Benign Tumors & Their Tissue of OriginPrefix Tissue Benign Tumor

NameAdeno- Gland AdenomaChondro- Cartilage ChondromaHemangio-

Blood vessels

Hemangioma

Hepato- Liver HepatomaLipo- Fat LipomaMyo- Muscle MyomaOsteo- Bone OsteomaFibro- Fibrous CT FibromaNeuro- Neural tissue Neuroma

Malignant tumors & their tissue of origin

Adenocarcinoma Glandular epithelium

Squamous cell carcinoma

Squamous epithelium

Osteosarcoma Bone

Chondrosarcoma Cartilage

Lymphosarcoma Lymph node

Liposarcoma Adipose tissue

Retinoblastoma Retinal tissue

Neuroblastoma Neural tissue

Nephroblastoma Renal tissue

Occupational carcinogens

Carcinogen Occupation Cancer type

Asbestos Construction Lung

Benzene Leather Leukemia

Benzidine Dye, rubber Bladder

Chromium Metal worker Lung

Arsenic Pesticides Lung,skin,liver

Tumor angiogenesis, Metastasis &Staging

Angiogenic factorsEndostatin- “Inhibits the angiogenesis

process”

MetastasisCommon location of metastasis

(Lung,liver,bone) The TNM (Tumor, Node and Metastasis)

system.It is one way of determining the prognosis of

the patient.

TNM system for Tumor grading

Primary

Tumor (T)

TX Primary tumor can not be evaluated

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1,T2,T3,T4 Size / extent of primary tumor

Regional

lymph Node (N)

NX Regional lymph node can not be evaluated

N0 No regional lymph node involvement

N1,N2,N3 Involvement of regional L.N(No./extent of spread)

Distant

Metastasis (M)

MX Distant metastasis can not be evaluated

M0 No Distant metastasis

M1 Distant metastasis

Carcinogen

Any substance at any dose, administered by any route, that increases tumor incidence. A carcinogen is a substance that is capable of causing cancer in humans or animals.GenotoxicNon-genotoxic

International Agency for research on cancer (IARC) Group A1: Carcinogenic to humans Group 2A: Probably Carcinogenic to humans Group 2B: Possibly Carcinogenic to humans Group 3: Not classifiable as to its Carcinogenicity to

humans Group 4: Probably not Carcinogenic to humans

Carcinogen Naturally-occurring microbial carcinogen (Aflatoxin

B1)

HBV,HPV, Rous sarcoma virus Dioxins and dioxin-like compounds Industrial smoke and tobacco smoke Vinyl chloride– Plastic industry Radiation (x-rays, gamma, infrared, ultraviolet

radiation) Co-carcinogens: are chemicals that do not

necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer (sodium arsenite)

Biotransformation: Less toxic----- more toxic

Carcinogen in food Cooking food at high temperatures, e.g.

grilling or barbecuing meats, can lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo pyrene).

Acrylamide is generated in fried or overheated carbohydrate foods (such as French fries and potato chips).

Milk protein Casein, found in milk and many prepared foods, is also a carcinogen. However, independent studies report that casein and other milk proteins protect against cancer.

Genotoxic Genotoxic carcinogens are DNA reactive or

DNA reactive metabolites capable of altering the integrity DNA through direct interaction:

Direct acting Carcinogens: Alkylating agents (Methyl chloromethyl ether) Indirect acting Carcinogens: Aflatoxin, polycyclic hydrocarbon

benz[a]pyrene.

Activation of chemical

Transport to Nucleus

Formation of a DNA adduct

Fixing

Mutation

NonGenotoxic They do not cause directly mutation of

DNA. The mechanism of action is poorly

understood. Not all carcinogens are mutagens. Carcinogenesis is often associated with

changes in methylation of DNA. Asbestos-related cancer associated with long latency periods,often decades

NonGenotoxic Diethylstilbestrol: vaginal and uterine

carcinoma Esterogen: breast cancer

Chemical induced carcinogenesis