2. Specific learning objectives
1. List the biochemical alterations in cancer cells
2. Explain what are protooncogenes?
3. Explain mechanisms by which they are activated to
cancer-producing oncogenes.
4. List the tumor suppressor gene.
5. Explain the mechanism of action of p53 gene product
6. List the functions of cyclins
7. List the antimetabolites and mention their uses
8. Say what are Tumor markers? Classify tumor markers
and mention their use.
3. What is Cancer ?
Derived from Latin word ‘cancrum’ meaning crab.
It is a group of diseases characterised by uncontrolled
cell division leading to the growth of abnormal tissue /
tumor.
4. Cell Proliferation
Cell multiplication (proliferation) - normal physiologic process
response to injury
immune responses
to replace cells that have died
to replace cells that have been shed as a part of their life cycle
(eg: skin, mucous membrane of GI tract, etc.,)
Kept at balance
Impairment of this balance leads to cancer
5. Oncology
Oncology branch of medicine deals with etiology,
diagnosis, treatment and prevention of cancer.
Onco is a Greek word meaning tumor
.
6. Types of Tumor
The uncontrolled and rapid proliferation of cells can lead to
either benign tumor or malignant tumor (cancer).
Benign tumors do not spread / invade
other parts of the tissues / body, and
they are rarely a threat to life.
Malignant tumors can invade
other organs, spread to distant
locations (metastasis) and become
life threatening.
7. Types of cancer
cancers can be classified by the type of cell in which it
originates and by the location of the cell.
.
cell Site / location cancer
Epithelial Digestive tract carcinoma
Blood cells WBC leukemia
lymphatic Lymph node lymphoma
Connective tissue bone sarcoma
melanocyte skin melanoma
Germ cells Testes/ovary Terratoma
8. Etiology of cancer
Multifactorial in origin:
Physical
Chemical
Biological (viruses )
Environmental factors (physical & chemical agents)
Hormonal
Genetic
Mutation
11. Initiation and Promotion in carcinogenesis
Skin tumor in mice
benzo(a)pyrene alone – no tumor
benzo(a)pyrene followed by several applications of
croton oil – many tumors develop
Application of croton oil alone – no tumors
Initiation: benzo(a)pyrene –rapid and irreversible
modification of DNA
Promotion: croton oil – slower process
Most carcinogens cause initiation and promotion
12. Mutation
Sudden change in the chemical structure of the DNA
- aberration in chemical structure
The substance which causes mutation is known as
‘mutagen’
Example:
X-ray
Gamma ray
UV ray
13. Oncogenic virus
Viruses which cause cancer are known as oncogenic virus
They can integrate their gene into the host DNA and take
over the entire regulatory mechanism of the host cell. The
host cell will produce viral genome instead of host genome
(transformed cell).
This leads uncontrolled multiplication of the host cells –
transformed cells.
14. Oncogenic virus..
SI No Virus cancer
1 Epstein-Barr virus
(EBV)
Nasopharyngeal
Burkitt’s lymphoma
2 Human Papilloma virus
(HPV)
Uterine Cervical
3 Hepatitis B virus
(HBV)
Hepatoma
15. Oncogenes
Genes which can cause cancer are known as oncognes.
Oncognes are present in normal cells also and in normal cells
they are known as proto-oncogenes
We have more than 100 proto-oncogenes on various
chromosomes
Example:
ras gene (sarcoma virus)
c-myc (avian myelocytoma virus)
16. Oncogenes..
Products of these oncognes are involved in the
regulation of cell cycle
These products may be growth regulating factor /
receptor
These oncogens are under the control of regulator
genes and expressed only when required.
Virus can carry these gene and transmit it to
individuals
17. Activation of Proto-oncogenes to
oncogenes
Promoter Insertion
Enhancer Insertion
Chromosomal Translocations
Chronic myeloid leukemia- Philadelphia chromosome
Chromosome 9(abl) and 22 (bcr),Reciprocal translocations
Burkitt’s lymphoma- Chromosome 8 (c-myc)and 14 (IgG)
Gene Amplification
Point mutation
19. Anti-oncognes / onco-suppressor gene
The genes which prevent cancer are known as anti-
oncogenes or onco-suppressor genes
The products of these genes act as breaks and
regulate cell proliferation
When these genes are deleted / mutated then it leads
cancer
20. Anti-oncogene /onco-suppressor gene
Anti-oncogene /
onco suppressor
gene
Cancer
(due to
mutation of the
gene)
p53 Breast cancer, colon
cancer
BRCA1 & BRCA2 Breast cancer
RB Retinoblastoma in
children
WT Wilms’ tumor
21. P53 tumor suppressor gene
53kDA – nuclear phosphoprotein - unstable
It can activate DNA repair proteins when
DNA has sustained damage.
It can arrest growth by holding the cell cycle
at the G1/S regulation point on DNA damage
recognition
It can initiate apoptosis
P53 P21 G1/S arrest
22. The mammalian cell cycle
G1
S
G2
M
G0
DNA synthesis and
histone synthesis
Growth and
preparation for
cell division
Rapid growth and
preparation for
DNA synthesis
Quiescent cells
phase
phase
phase
phase
Mitosis
23. Cyclins in cell cycle progression
Cyclin Kinase Function
D CDK4,
CDK6
Progression past G1/S
boundary
E,A CDK2 Initiation of DNA synthesis in
early S phase
B CDK1 Progression from G2 to M
24.
25. Telomerase and cancer
Active in cancer cells and proliferating normal cells
RNA primer at 5’end of newly synthesized strands
cannot be replaced with DNA
Shortening of the ends of chromosomes at each
replication, with loss of important genes
In humans telomeres consist of 1000 or more arrays
of TTAGGG repeats at the 3’ ends
Genomic stability in germ-line cells is maintained by
Telomerase
26. Characteristics of cancer cells
1. uncontrolled proliferation
2. abnormal nucleus
3. loss of anchorage
4. disorganized multilayer (loss of contact inhibition)
5. forms tumor
6. undergoes metastasis & angiogenesis
7. lack of differentiation into specialized cells.
8. increased rate of anaerobic glycolysis
27. Cancer cells: Biochemical changes
Increased synthesis of DNA & RNA
Increased rate of aerobic and anaerobic glycolysis to
meet the increased demand for energy for more
cells.
the rate of anaerobic glycolysis is tremendously
increased
28. Normal cell Cancer cell
Controlled cell proliferation Uncontrolled proliferation
Contact inhibition No Contact inhibition
Normal nucleus Abnormal nucleus
Organised , single layer Disorganised, multilayer
Differentiated cells Non differentiated cells
---- Metastasis & angiogenesis
apoptosis
Does not undergo apoptosis
telomerase activity stops
after about 50 cell cycles
Increased & persistent
telomerase activity
29. Standard cancer treatment
Surgery:
removal of cancerous tissue
Radiotherapy:
destruction of cancer cells using
radioactive rays
Chemotherapy:
killing cancerous cells using drugs
30. Antimetabolites/Anticancer drugs
Anticancer drug chemistry Mechanism of action
methotrexate Folic acid analogue Inhibits
dihydrofolate reductase (THF)
6-mercaptopurine Purine analogue Inhibits formation of AMP
6-thioguanine Purine analogue Inhibits
thymidylate synthesis
Mitomycin C antibiotic Linking DNA base pairs
Actinomycin D antibiotic Inhibits transcription
cisplatin Platinum compound Forms DNA adducts
Vinblastine &
vincristine
alkaloids Inhibits spindle movement
(mitosis)
31. Cancer prevention: Antioxidants
Prevents / scavenges free radicals.
Can detoxify carcinogens
Antioxidant vitamins:
Vitamin A
Vitamin E
Vitamin C
Vegetables & fruits
33. Ideal tumor marker
Must be produced by tumor cells
Should not be present in normal / healthy / benign
condition
Must be detectable in body fluids
It could be used for screening the presence of cancer
in asymptomatic patients.
34. Tumor marker:
Criteria for diagnostic marker
1. Highly specific
2. Highly sensitive
3. able to differentiate between neoplastic & non neoplastic
diseases
4. increase in level should precede neoplastic process
36. Tumor marker: classification
Tumor markers are classified into various groups:
Enzymes
Hormones
Proteins
Oncofoetal antigen
Genes
Carbohydrate antigen
Blood group antigen
Receptors
37. Oncofoetal antigens
Oncofoetal antigens are proteins produced during
foetal life and present in high concentration during
foetal life and decreased to low concentration and
disappears after birth.
This protein will reappear in cancer patients
Alpha foetoprotein (AFP)
Carcinoembryonic antigen (CEA)
38. Alpha foetoprotein (AFP)
It’s molecular weight is 70000
It is foetal albumin & resembles with adult albumin
It’s normal level in adult: less than 10ug / L
More than 300 ng / L is associated with cancer
It’s level is Elevated in:
Hepatocellular carcinoma
Pregnancy with foetal abnormality (neural tube defect)
Germ cell tumor
Elevated level is also seen in:
Hepatitis, cirrhosis & pregnancy.
39. Carcinoembryonic antigen (CEA)
It consists of large family of cell surface glycoprotein.
It’s molecular weight is ranging from 150 to 300 KD
It is normally produced by the embryonic tissue of
liver, pancreas & gut.
It level is elevated in:
Colorectal cancer, Gastrointestinal cancer, Pancreatic
cancer
Lung cancer, Breast cancer, Ovarian cancer, Uterine
cancer
40. Tumor marker: Enzymes
first group of tumor markers identified
ALP: primary / secondary involvement of liver cancer.
High level of ALP is also seen in secondary
involvement of bone cancer
Gamma glutamyl transferase (y-GGT) &
5’- Nucleotidase (5-NT) are also used to
diagnose liver cancer.
Prostatic Acid Phosphatase (PAP): it is elevated
in prostatic cancer.
Prostate specific antigen (PSA) is more
specific and sensitive than Acid
phosphatase
41. Tumor marker: Hormones
Hormone is used as tumor marker in the following
conditions:
High level of hormone is secreted by the endocrine
tissues where it is normally secreted.
secreted by a non endocrine tissues where it is
normally not secreted - ectopic syndrome
42. Hormones as tumor marker
Hormone cancer site
ACTH
(pituitary)
lung ectopic
Calcitonin
(C cells of
thyroid)
Medullary thyroid ectopic
Parathyroid hormone
(parathyroid gland)
Breast, liver, lung,
etc.
ectopic
ADH
(posterior pituitary)
Adrenal cortex,
pancreatic &
duodenal
ectopic
Epinephrine
(adrenal medulla)
Pheochromocytoma normal
43. β Human Chorionic Gonadotropin
(β -hCG)
It is synthesised by trophoblast of placenta
It is a glycoprotein and its molecular weight is 45 KD
It has two dissimilar subunits
It’s alpha submit is identical with FSH, LH & TSH
Beta subunit is specific for HCG
Normal value is less than 20 IU / L
It’s level is elevated in:
trophoblastic tumour
choriocarcinoma
Germ cell tumor
44. Tumor marker: Protein
Prostate specific antigen (PSA): it is useful in diagnosis
of prostate cancer
Bence- Jones Proteins: plasma cell from B-lymphocyte
proliferates and produces light chain immunoglobulin known
as M-protein (paraprotein).
It is used for diagnosis of multiple myeloma
It has characteristic property towards heat treatment.
It is precipitated at 50o
- 60o
C and re dissolves at 90o
C. On
cooling, it again precipitates
45. Carbohydrate antigen (CA 125)
It is a glycoprotein & Mol wt : 10 million
Normal level is less than 35 U / ml.
It is elevated in:
Ovarian cancer
Pancreatic cancer
GI tract cancer
46. Tumor marker: gene
Oncogenes can be used as tumor markers:
oncogene cancer
ras Sarcoma
c-myc Leukemia & lymphoma
47. Tumor marker: gene
Antioncogenes as tumour markers:
Tumor suppressor gene cancer
p53 Breast cancer &
colon cancer
BRCA1 & BRCA2 Breast cancer
RB retinoblastoma
48. Receptors
Estrogen & Progesterone receptors (ER & PR) are useful as
prognostic indicator and also to decide hormonal therapy in
breast cancer
ER positive tumor tissue necessitate hormonal treatment for
effective treatment
PR assay is a useful adjunct to ER assay for breast cancer.
