Biochemistry of cancer AND effect of factors on cancer growth.ppt

CANCER BIOCHEMISTRY, MEDICINE, TREATMENT AND DETAILS OF CANCER, MBBS AND PARAMEDICAL TEACHING,
CANCER AETIOLOGY, DETAILED GROWTH MECHANISMS,

1. Biochemistry of cancer
Cancer-Cellular tumor that can metastasize
and invade surrounding and distant tissue.
Properties
•Diminished or restricted control of growth
•Capability of invasion of local tissues
•Capable of spreading to distant parts of body
by metastasis

2. Certain genes, controlling growth and interactions
with normal cells ,are apparently abnormal in structure
or regulation in cancer cells.
Study focused around ONCOGENES, TUMOR
SUPPRESOR GENES, GROWTH FACTORS &THEIR
RECEPTORS, DNA REPAIR SYSTEMS &REGULATION OF
CELL CYCLE.

3. Characteristics of cancer cell
Morphology
-Rounded shape , larger than normal cells
-Nuclear and cellular pleomorphism
-Hyperchromatism
-Altered nuclear : cytoplasmic ratio
-Form multilayer
-Reduced surface attachment

4. Biochemical changes in cancer
cell
•Increased synthesis of DNA and RNA
•Increased rate of glycolysis
•Altered permeability and surface charge
•Altered glycoprotein and sphingolipids on cell surface
•Increased activity of ribonucleotide reductase and
decreased catabolism of pyrimidines

5. •Altered isoenzyme patterns often to fetal pattern and
synthesis of fetal proteins. eg. CEA,AFP
•Appearance of new antigens and loss of certain
antigen
•Inappropriate synthesis of certain hormones and
growth factors.

6. Etiology of cancer
Predisposing factors
Age> 55 years
< 15 years –
-retinoblastoma, leukaemias,
lymphoma, neuroblastoma, wilms tumor
Hereditary :
Retinoblastoma –AD
Multiple colonic polyposis –AD

7. Envirnomental factors
Lifestyle: cigarette smoking, tobacco
Dietary: aflatoxin B
1 from groundnut
Occupational : asbestos ,beryllium
Iatrogenic : drugs
Acquired precancerous disorders
Leukoplakia
Cirrhosis of liver
Ulcerative colitis

8. Carcinogenic agents
Physical: Radiation energy
Chemical: Carcinogenic or procarcinogen
Biological: Oncogenic viruses
Radiation –
X-rays , γ-rays , UV rays
Direct effect–damage to DNA
-Single or double stranded breaks
-Elimination of bases
-Cross-linking of strands
-Formation of pyrimidine dimers

9. Indirect effects
-Free radical formation
UV rays
–skin cancer (melanoma /carcinoma )
-Pyrimidine dimers
-Immunosuppresion
Ionizing radiations
Particulate radiations(α-particle & neutrons)
-more carcinogenic than electromagnetic radiations.

10. Routes to Genetic Instability based on
Defective DNA Repair

11. Chemicals as carcinogens
Class
1.Polycyclic aromatic
hydrocarbons
2.Azo-dye
3.Nitrosamines and
amides
4.Naturally occurring
compounds
5.Drugs
6.Inorganic compound
Chemical compounds
-Benzene , Dimethyl
benzanthracene
-β-Napthylamine
-Dimethyl nitrosamines
-Diethyl nitrosamine
-Aflatoxin B
1
-Alkylating/acylating
agents e.g.. busulfan &
Cyclophosphamide
-Beryllium, cadmium,
nickel, asbestos

12. Mechanism of chemical
carcinogenesis
Direct acting
e.g.. Busulfan ,Cyclophosphamide
Procarcinogen
procarcinogen → proximate carcinogen
↓ cytochrome P
450
ultimate carcinogen
-Exert electrophilic attack on nucleophilic DNA, RNA
& protein.
-Bind covalently to cellular macromolecules-DNA,RNA,
Proteins
-I/A with purine , pyrimidine & phosphodiester bond
-Common site -guanine

13. Most chemical carcinogens are MUTAGENS
At molecular level may cause-TRANSITIONS,
TRANSVERSIONS & OTHER TYPES OF MUTATIONS.
Some Cancers due to mutations in somatic cells that
effect key regulatory processes in these cells

14. DNA IS CRITICAL MOLECULE
IN CARCINOGENESIS
Supported by many observations
Cancer cells beget cancer cells.
Both IRR & Chem. carc damage DNA & cause
mutations in DNA.
Many tumor cells exhibit abnormal chromo.
Purified DNA from cancer cells can transform normal
cells to potential cancer cells.
Genes that increase susceptibility to cancer have been
isolated.

15. VIRAL ONCOGENESIS
Oncogenic viruses contain either DNA or RNA as their
genome.
Virus linked human cancers----15% of total cancer
incidence.

16. SOME IMPORTANT TUMOR
VIRUSES
 CLASS
DNA VIRUSES
PAPILOMAVIRUS
ADENOVIRUS
HERPESVIRUS
HEPADNAVIRUS
 MEMBER
POLYOMA, PAPILLOMA, SV 40
VIRUS
ADENOVIRUS 12,18 ,31.
EPSTEIN-BARR VIRUS
HEPATITIS B VIRUS

17. RNA VIRUS
RETROVIRUS TYPE C
RETROVIRUS TYPE B
MURINE SARCOMA &
LEUK VIRUS, AVIAN
SARCOMA &LEUK VIR,
HUMAN T CELL LEUK
VIRUSES l & ll
MOUSE MAMMARY
TUMOR VIRUS

18. DNA viruses
HPV-warts → skin cancer , carcinoma cx
HBV-Hepatic carcinoma
EBV -Burkitt ̓s lymphoma , nasopharyngeal
carcinoma
RNA viruses (retrovirus )
Human T-cell leukaemia virus (HTLV) –
leukaemia , lymphoma
Avian sarcoma virus
Murine sarcoma virus

19. ONCOGENES PLAY A CRUCIAL
ROLE IN CARCINOGENESIS
ONCOGENES ARE GENES CAPABLE OF CAUSING
CANCER.
FIRST RECOGNISED AS UNIQUE GENES OF TUMOR
CAUSING VIRUSES THAT ARE RESPONSIBLE FOR THE
PROCESS OF TRANSFORMATION.

20. ACTIVATED ONCOGENES INFLUENCE CELLULAR
GROWTH
a)BY DISTURBING NORMAL CELLULAR MECHANISM OF
GROWTH CONTROL
b)BY ACTING AS GROWTH FACTORS OR RECEPTORS
c)BY CERTAIN OTHER MEANS

21. PROTO-ONCOGENES
Proto-oncogenes are normal genes required for normal
functions in development and/or homeostasis, that
serve as precursors of genes that can gain the ability
to be dominant-acting oncogenes
Change in genetic coding sequence leads to new or
accelerated biochemical activity

22. ONCOGENES & TUMOR
SUPPRESSOR GENES
Oncogenes arise from proto-oncogenes either by
viral infections or by exposure to carcinogenic
agents.
Activation of proto-oncogenes or inactivation of
tumor suppressor genes can lead to cancer.
Tumor suppressor genes function by loss of
function mutations

23. Five Mechanisms for converting Proto-oncogenes
into Oncogenes

24. MECHANISM OF ACTION OF
ONCOGENES
1) T protein (T antigen)
bind DNA –alter gene expression
2) Vinculin –protein involved in intercellular
adhesion.
3) Tyrosine kinase –Abn phosphorylation of
protein at Tyrosine
4) Phosphorylation of phosphatidylinositol to
mono & bisphosphate

25. CELLULAR ONCOGENES
c-onc
Oncogene chr virus product
1.abl 9 abelson leukemia vrs Tyrosine kinase
2.erb-B 7 avian erythroblastosis vrs EGRF
3.erb-A 17 -do- TGF-R
4.myc 8 myelocytoma virus DNA-bindg protein
5.sis 22 simian sarcoma virus PDGF
6.src 20 rous sarcoma virus Tyrosine kinase
7.ras 12 murine sarcoma virus GTPase

26. GROWTH FACTORS
THEY EXERT A MITOGENIC RESPONSE ON THEIR
TARGET CELLS
AFFECT MANY DIFFERENT TYPES OF CELL e.g.
BLOOD ,NERVOUS SYSTEM , MESENCHYMAL TS,
EPITHELIAL CELLS.
GROWTH INHIBITORY FACTORS INHIBIT THE
GROWTH OF CERTAIN CELLS
THUS, CHRONIC EXPOSURE TO INCREASED
AMOUNT OF GROWTH FACTORS OR DECREASED
AMOUNTS OF GROWTH INHIBITORY FACTORS CAN
ALTER THE BALANCE OF CELLULAR GROWTH.

27. GF ACT VIA
TRANSMEMBRANE SIGNAL
TRANSDUCTION
MAY ACT IN AN ENDOCRINE, PARACRINE OR
AUTOCRINE MANNER.
MOST HAVE HIGH AFFINITY PROTEIN RECEPTORS ON
PM OF TARGET CELLS.
NO OF RECEPTORS(FOR EGF, INSULIN &PDGF)----PR
TYR KINASE ACTIVITY---AUTOPHOS OF RECEPTOR
PROTEIN &PHOSPH OF OTHER PR .

28. SOME POLYPEPTIDE GF
GROWTH FACTOR
EGF
ERYTHROPOIETIN
IGF-1 & IGF-II
IL-1 & IL-2
NERVE GROWTH FACTOR
PDGF
TGFα
TGFβ
SOURCE
MOUSE SALIV GLAND
KIDNEY, URINE
SERUM
CONDITIONED MEDIA
MOUSE SALIV GLAND
PLATELETS
COND MEDIA OF TUMOR
CELLS
KIDNEY,PLATELETS

29. Overview of Carcinogenesis

30. Chr translocation that creates Philadelphia Chr
BCR-ABL Oncogene : Breaks in ABL Gene of Chr 9 &
BCR Gene of Chr 22
Fusion Protein causes Chronic Myelogenous Leukemia

31. Point Mutation in a RAS Oncogene

32. Oncosuppressor genes
Name Abb chr no.
1.Retinoblastoma RB 13
2.Wilm’s tumor WT 11
3.Familial adenomatous FAP 05
polyposis
4.Deleted in colon cancer DCC 18
5.Gene for p53 p53 17
6.Familial breast cancer BRAC 3
7.VHL gene VHL 3

33. DIFFERENCES B/W
ONCOGENES &TUMOR
SUPPRESOR GENES
ONCOGENES
MUT IN ONE OF THE TWO
ALLELES SUFFI FOR
ACTIVITY;ACT DOMINAN
TO WILD TYPE.
GAIN OF FUNCT OF A PR
THAT SIGNALS CELL DIV.
MUT ARISES IN SOMATIC
TS, NOT INHERITED.
SOME TS. PREFRENCES.
TUMOR SUPP GENES
MUT IN BOTH ALLELES OR
MUT IN ONE FOLLOW BY
LOSS OF OR REDUCT OF
HOMOZYG IN SECON.
LOSS OF FUNCT OF A PR.
MUT +NT IN GERM CELL
(CAN BE INH.)OR SOMATIC
CELL.
STRONG TS PREFRENCES
(e.g. RB1FOR RETINA)

34. RETINOBLASTOMA
MAL TU OF RETINAL NEUROBLAST--> PRECURSOR
CELLS OF PHOTOREC CELLS.
IN SOME CASE INHERITED ; IN OTHER CASES DOES
NOT APPEAR TO BE HEREDI.
IN 1971 KNUDSON SUGGESTED THAT ITS DEV
DEPENDED ON 2 MUTATIONS.
IN HERD CASES 1 MUT +nt IN GERM CELLS & 2
OCCURRED IN RETINOBLAST.

35. IN SPORADIC CASES BOTH MUTATIONS OCCURRED IN
RETINOBLAST.
ANALYSIS OF RB1 GENE IN HERDI. CASE
HETEROZYGOSITY (1 NORMAL & 1 ABN ALLELE) BUT
ANALY OF THE TUMOR SHOWED HOMOZYGOSITY IN
THIS REGION LOSS OF HETEROZYGOSITY

36. Knudson’s “Two-Hit” Model
for Retinoblastoma

37. INACTIVATION OF p RB-IMP FACTOR IN SMALL CELL
LUNG CANCERS, ADENOCARCINOMA OF THE
PROSTATE AND TUMORS ORIGINATING FROM RETINA,
BONE & CONNECTIVE TS.

38. p -53 TUMOR SUPPR. GENE-
GUARDIAN OF THE GENOME
V IMP TU SUPPR GENE LOCATED ON SHORT ARM OF
Chr 17.
PRODUCT (p-53) IS A NUCL PHOSPHOPR OF 53 KDA.
HAS 3 MATOR EFFECTS
1.ACTS AS TRANSCRIPTIONAL REGULATOR,
REGULATING CERTAIN GENES INVOLVED IN CELL
DIVISION.
2.ACTS AS A G1 CHECK POINT CONTROL FOR DNA
DAMAGE.

39. EXCESS DNA DAMAGE-ACTIVITY OF p-53
INCREASES RESUTING IN INHIBITION OF CELL DIV
AND ALLOWING TIME FOR REPAIRGAURDIAN OF
GENOME.
3. PARTICIPATES IN INITIATION OF APOPTOSIS, THUS
HASTENING THE DEATH OF POTENTIALLY
DANGEROUS CELLSGAURDIAN OF TISSUES.

40. How p53 protein responds to DNA damage?
p53 protein is either degraded or converted to p53-P
which
triggers: 1) cell cycle arrest for DNA repair or; (2) If DNA
is not
repaired then promotes apoptosis

41. MAJOR FEATURES OF p-53
MUTATIONS IN HUMAN
TUMORS
MOST COMMON GENETIC ALTERATIONS IN HUMAN
CANCER & ARE FREQUENT IN COLON, BREAST &
LUNG CANCER.
ATLEAST 100 DIFFERENT MUTATIONS HAVE BEEN
DETECTED IN THIS GENE.
MUT USUALLY FOUND AT HIGHLY CONSERVED
CODONS

42. TELOMERES AND TELOMERASE
Telomeres –
-ends of chromosome
-TG-rich
-maintained by telomerase
Function -stability of ends
Telomerase–“ telomere terminal transferase”
-reverse transcriptase
Role in ageing-telomere shortening lack of telomerase
activity.
Role in cancer-telomerase is present in cancer cells.
Telomerase activity–staging of tumors for which no markers are
available.

43. Antimutagens
Vitamin A & carotenoids (lycopene)
Vitamin C
Vitamine E
Selenium
Zinc
Curcumin
Fibre content in diet
Low fat ,low protein diet
Green leafy vegetables

44. BIOCHEMISTRY OF
METASTASIS

45. Characteristics of Benign and
Malignant Tumors

47. Malignancy requires
1.Cells lose adhesion with the initial tumor
2.Cells migrate out of the initial tumor
3.Cells enter the bloodstream/lymphatic
systems
4.Cells exit the bloodstream/lymphatic
system
5.Cells are able to form new tumor foci

48. Tumor angiogenesis
Without angiogenesis, tumor size is limited

49. Stimulators of
Angiogenesis
•VEGF: Vascular Endothelial Growth Factor
•Growth factors:FGF, EGF, PGF, PDGF
•Cytokines:IL 8, TNFα, TGFα
•Small Molecules:Adeonosine, Nicotinamide,
Prostaglandins.

50. Angiogenesis is a target for
chemotherapy

51. Matrix Metalloproteinases (MMPs)
Zn2+ and Ca2+ dependent proteases.
Degrade protein components of the extracellular
matrix, basement membrane.
Release and activate growth factors from ECM
stores.
Cleave proteins to reveal cryptic sites.
Activity required for tissue remodeling and
repair.
Over/inappropriate expression associated
carcinogenic progression

55. Anticancer drugs
Name type mode of action
1.Methotrexate folic acid analogue cmp inh of DHF R
2.6-mercaptopurine purine analogue inh IMP-AMP
3.6-thioguanine purine analogue inh thym synthase rxn
4.Cyclophosphamide alkylating agent cross linking of bases
in DNA
5.Mitomycin C antibiotic cross brigdes of bases
in DNA

56. Name type mode of action
Actinomycin D antibiotic intercalates
with guanine
Vincristine & alkaloids from interferes with
Vinblastine vinca rosea spindle movement
Adriamycin anthracycline topoisomerase
mediated breaks
Etoposide podophyllotoxin stabilises
topoisomerase-11 breaks
cisplatin platinum compound form intrastrand DNA
adducts

57. Drug resistance
Mechanism of drug resistance
1.Target enzyme pathway is deleted
2.Alternate minor pathway of drug metabolism
3.Drug uptake reduced
4.Multidrug resistance –P-glycoprotein (ATP
dependent efflux pump of drugs)
5.Increased synthesis of enzyme degrading the
drug

58. Metastasis suppressor genes
CAD1gene:for E-cadherin
Metastasis promoting genes
Twist gene : Twist protein
For losing cells adhesive properties
-Inhibitor of Twist: inhibition cell metastasis

59. Biochemical substances
•Synthesized and released by cancer cells.
•Produced by host in response to cancerous
substances.
•Used to monitor cancerous growth.

60. Clinical uses of tumor markers
1.Screening
2.Diagnosis
3.Prognostic predictor
4.Clinical staging of cancerous condition
5.Monitoring during treatment
6.Early detection for relapse

61. Characteristics of an ideal tumor marker
High senstivity
High specificity
High accuracy
High precision
Simple and easy to measure
Should not be very costly

63. Alpha-Fetoprotein in HCC
Glycoprotein ,found in fetal liver, yolk sac, GI tract,
biochemically related to albumin in adults
Half-life：4~6 days
Normal serum levels：
12~15th gestational week 30~40ng/ml
At birth 30ng/ml
>1 years old (adult) <20ng

64. Increased in 70% HCC, elevated in hepatoblastoma,
20~70% germ cell tumors(yolk sac tumors, embryonal
cell carcinoma) of testis and ovary, except dysgerminoma
For Hbs Ag (+) chronic hepatitis/cirrhosis screening.
The absolute AFP level correlates with tumor bulk
CSF：plasma ratio of AFP > 1:40 → suggest CNS
involvement
Benign：conditions that cause hepatic parenchymal
inflammation, hepatic necrosis and hepatic regeneration,
ex. hepatitis, pregnancy, primary biliary cirrhosis,
extrahepatic biliary obstruction

65. Carcinoembryonic antigen (CEA)
Fetal glycoprotein found on cell surfaces, produced by fetal GI tract, liver,
and pancreas
Normal serum and tissue fluid value：<3.0 ng/ml
Circulating half-life：weeks
Detect early relapse of colorectal cancer and prognostic indicator

66. Carcinoembryonic antigen (CEA)
Normal pretherapy CEA：lower metastasis incidence
High initial CEA：higher metastasis incidence
In 2/3 of patients an elevated CEA may be the 1
st
indication of relapse

67. Found also in 30~50% of breast cancer, small
cell lung cancer, mucinous
cystadenocarcinoma of ovary,
adenocarcinoma of cervix
Elevation (<10 ng/ml) in smokers, COPD,
inflammatory or peptic bowel disease, liver
inflammation or cirrhosis, renal failure,
fibrocystic breast disease

68. Detection
Monitor treatment response (ex. C/T)：production of
BHCG ceases on commencement of tx, rising or
persistently elevated levels are diagnostic of resistance to
C/T
evaluate radicality of the surgery: ex. In testicular cancer,
the presence of β-HCG after orchiectomy → residual
cancer and needs further treatment
Monitor relapse (reliable indicator of CR)

69. PSA
Tissue specific antigen, produced by prostatic alveolar
and ductal epithelial cells , a serine protease, t 1/2：2~3
days
Relapse
Reflect response to treatment and correspond to tumor
volume and androgen level
As a predictor of surgical failure：by using RT-PCR for PSA
to detect circulating prostate cancer cells in the
bloodstream

70. Age Serum PSA (ng/ml)
40~50 0~2.5
50~60 0~3.5
60~70 0~4.5
70~80 0~6.5

71. PSA is expected to be undetectable >30 days after the radical
prostatectomy, persistent elevated level indicate residual disease
Free PSA：PSA that is not bound to the plasma
antiproteases α1-antichymotrypsin and α2-macroglobulin
An ↑in ratio of free/total PSA is associated with increased probability of
prostate cancer

72. 97% specific for this disease, 96% sensitivity in detecting disease
For population screeningand diagnosis：an increase of 0.75 ng/ml per
year in any given patient has high sensitivity and specificity for prostate
cancer vs BPH, especially when combined with DRE and TRUS

73. Human chorionic gonodotropin
(βHCG)
Glycoprotein synthesized by syncythiotrophoblastic cells
of normal placenta, never in males!
Serum and urine HCG ↑in early gestation and peak in the
first trimester (60~90 days)
T ½: 1.25 days, ~30 hours
Elevated in：gestational trophoblastic disease(a
progressive rise in after 90 days of gestation → highly
suggestive), choriocarcinoma