MOLECULAR PATHOGENESIS OF CANCER(GENES
AND CANCER)
GENETIC THEORY OF CANCER.
CELL GROWTH OF NORMAL AS WELL
AS ABNORMAL CELL IS
UNDER GENETIC CONTROL
MOLECULAR PATHOGENESIS OF
CANCER(GENES AND CANCER)
IN CANCER ABNORMALITY MAY BE
INHERITED OR AQUIRED-INDUCED BY
CHEMICALS,VIRUSES OR RADIATION.
MUTATED CELL TRANSMIT THEIR
CHARACTERS TO THE NEXT
PROGENY OF CELLS AND RESULT IN
CANCER.
GENETIC REGULATION OF NORMAL
AND ABNORMAL MITOSIS
NORMAL CELL GROWTH
REGULATORY GENES CONTROL
MITOSIS AS WELL AS CELL
AGING
GENETIC REGULATION OF NORMAL
AND ABNORMAL MITOSIS
REGULATORY GENES ARE
1.PROTO-ONCOGENES- GROWTH
PROMOTING GENES.
2.ANTI-ONCOGENES- GROWTH
SUPPRESSOR GENES
GENETIC REGULATION OF NORMAL
AND ABNORMAL MITOSIS
3.APOPTOSIS REGULATORY GENES
4.DNA REPAIR GENES- REPAIR DNA
DAMAGE THAT HAS OCCURED
DURING MITOSIS AND ALSO
CONTROL THE DAMAGE TO
PROTOONCOGENES AND
ANTIONCOGENES
ABNNORMALITIES OF GENES IN
CANCER
a.ACTIVATION OF GROWTH
PROMOTING ONCOGENES.
ABNORMALITIES OF GENES IN
CANCER
MUTANT FORM OF NORMAL
PROTOONCOGENE IN
CANCER IS TERMED
ONCOGENE.
ABNORMALITIES OF GENES IN
CANCER
b. INACTIVATION OF CANCER
SUPPRESSOR GENESPERMITTING CELLULAR
PROLIFERATION OF
TRANSFORMED CELLS.
ABNORMALITIES OF GENES IN
CANCER
c. ABNORMAL APOPTOSIS
REGULATING GENES WHICH
MAY ACT AS ONCOGENES
d. FAILURE OF DNA REPAIR
GENES.
ABNORMALITIES OF GENES IN
CANCER
CANCER GROWTH AND
PROGRESSION IS A MULTISTEP
PROCESS INVOLVING MANY
GENERATIONS OF
CELLS.VARIOUS CAUSES MAY
ACT ON THE CELL ONE AFTER
ANOTHER (MULTIHIT PROCESS).
ABNORMALITEIS OF GENES IN
CANCER
THE CELLS SO FORMED ARE
GENETICALLY AND PHENOTYPICALLY
TRANSFORMED CELLS HAVING
PHENOTYPIC FEATURES OF
MALIGNANCY- EXCESSIVE
GROWTH, INVASIVENESS, AND
DISTANT METASTASIS.
CANCER RELATED GENES AND
CELL GROWTH
MAJOR GENETIC PROPERTIES OR
HALL MARKS OF CANCER ARE.
1.EXCESSIVE AND AUTONOMOUS
GROWTH:GROWTH PROMOTING
ONCOGENES.
2.REFRACTORINESS TO GROWTH
INHIBITORY- GROWTH SUPPRESSING
ANTIONCOGENES.
CANCER RELATED GENES AND
CELL GROWTH
3.ESCAPING CELL DEATH BY
APOPTOSIS - GENES
REGULATING APOPTOSIS.
4.AVOIDING CELLULAR AGINGTELOMERES AND TELOMERASE
5.CONTINUED PERFUSION CANCER ANGIOGENESIS
MAJOR GENETIC PROPERTIES
AND HALL MARKS OF CANCER
6. INVASION AND DISTANT
METASTASIS-CANCER
DISSEMINATION.
7. DNA DAMAGE AND
FAILURE OF REPAIR SYSTEM
MAJOR GENETIC PROPERTIES
AND HALL MARKS OF CANCER
8. CANCER PROGRESSION,
TUMOUR HETEROGENEITY
AND CLONAL
AGGRESSIVENESS.
MAJOR GENETIC PROPERTIES
OR HALL MARKS OF CANCER
MECHANISM OF ACTIVATION OF GROWTH
PROMOTING ONCOGENES IN HUMAN
TUMOURS
1. POINT MUTATION ( SINGLE
BASE SUBSTITUTION)
EXAMPLE –RAS ONCOGENE IN
HUMAN TUMOURS SUCH AS
BLADDER CANCER,
PANCREATIC
ADENOCARCINOMA.
MECHANISM OF ACTIVATION OF GROWTH
PROMOTING ONCOGENES IN HUMAN
TUMOURS
2. CHROMOSOMAL
TRANSLOCATION
TRANSFER OF A PORTION OF
ONE CHROMOSOME TO ANOTHER
IS IMPLICATED IN THE
PATHOGENESIS OF LEUKEMIAS
AND LYMPHOMAS
MECHANISM OF ACTIVATION OF GROWTH
PROMOTING ONCOGENES IN HUMAN
TUMOURS (TRANSLOCATION)
PHILADELPHIA CHROMOSOME IN
CHRONIC MYELOID LEUKEMIASABL PROTOONCOGENE ON
CHROMOSOME 9 IS
TRANSLOCATED TO
CHROMOSOME 22(95% OF CML).
PHILADELPHIA CHROMOSOME
MECHANISM OF ACTIVATION OF GROWTH
PROMOTING ONCOGENES IN HUMAN
TUMOURS (TRANSLOCATION)
BURKITTS LYMPHOMATRANSLOCATION OF C-MYC
PROTOONCOGENE FROM IT’S
SITE ON CHROMOSOME 8 TO
CHROMOSOME 14
MECHANISM OF ACTIVATION OF GROWTH
PROMOTING ONCOGENES IN HUMAN
TUMOURS (TRANSLOCATION)
3. GENE AMPLIFICATIONINCREASE IN NUMBER OF
COPIES OF A GENE FOUND IN
SOME SOLID HUMAN TUMOURS.
HOW ONCOGENES ACT ?
BY SIGNAL TRANSDUCTION
FOR CELL PROLIFERATION.
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES-IN RELATION TO
MITOSIS.
1. GROWTH FACTORS IN
CANCER.
GFs ELABORATED BY MANY
CELLS HAVING PARACRINE
ACTION,BUT IN CANCER THEY
HAVE AUTOCRINE ACTION AS
WELL.
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES
2.RECEPTORS FOR GROWTH
FACTORS.-ARE CODED BY
ONCOGENES-
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES
HER2(ERB2) – GF RECEPTOR
OVEREXPRESSED IN BREAST
CANCER,
CARCINOMA LUNG,OVARY
AND STOMACH
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES IN RELATION TO
MITOSIS- SIGNAL TRANSDUCTION PROTEINS
3 .SIGNAL TRANSDUCTION
PROTEINS -TRANSDUCE SIGNALS
FROM GF RECEPTORS ON THE
CELL SURFACE TO THE NUCLEUS
OF THE CELL- MUTATED IN SOME
CANCERS.
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES IN RELATION TO
MITOSIS- SIGNAL TRANSDUCTION PROTEINS
EXAMPLES
a . RAS GENE- ONE THIRD OF
ALL HUMAN TUMOURS CARRY
MUTATED RAS- CARCINOMA
COLON,LUNG,PANCREAS
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES(SIGNAL
TRANSDUCTION PROTEINS)
NORMAL RAS PROTEIN IS
INACTIVATED BY GTPase.BUT
MUTATED FORM OF RAS GENE
REMAIN UNAFFECTED BY
GTPase,SO CONTINUE TO REMAIN
ACTIVE TO SIGNAL FOR CELL
PROLIFERATION.
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES(SIGNAL
TRANSDUCTION PROTEINS)
b. BCR-ABL HYBRID GENE- ABL
PROTO-ONCOGENE FROM IT’S
NORMAL LOCATION ON
CHROMOSOME 9 IS TRANSLOCATED
TO CHROMOSOME 22 WHERE IT
FUSES WITH BCR(BREAKPOINT
CLUSTER REGION) GENE .
•
STEPS IN SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES(SIGNAL
TRANSDUCTION PROTEINS)
THIS HYBRID GENE IS MORE
POTENT IN SIGNAL
TRANSDUCTION PATHWAYCML,CERTAIN ACUTE
LEUKAEMIAS.
SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES IN
RELATION TO MITOSIS
4. NUCLEAR REGULATORY
TRANSCRIPTION PROTEINS SIGNAL TRANSDUCTION
PATHWAY REACHES NUCLEUS
WHERE IT REGULATES DNA
TRANSCRIPTION.
SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES IN
RELATION TO MITOSIS
MOST IMPORTANT
REGULATORY TRANSCRIPTION
PROTEIN IS MYC PROTEIN WHICH
BINDS TO DNA REGULATES CELL
CYCLE BY TRANSCRIPTIONAL
ACTIVATION.
SIGNAL TRANSDUCTION FOR CELL
PROLIFERATION BY ONCOGENES IN
RELATION TO MITOSIS
OVEREXPRESSION OF MYC
ONCOGENE CAUSES
AUTONOMOUS CELL
PROLIFERATION.
SIGNAL TRANSDUCTION- NUCLEAR
REGULATORY TRANSCRIPTION PROTEINS
EXAMPLE-BURKITT’S LYMPHOMAMUTATION IN MYC ONCOGENE IS DUE
TO TRANSLOCATION 8:14
AMPLIFICATION OF MYC GENE IN
CARCINOMA LUNG ,BREAST ,COLON
SIGNAL TRANSDUCTION- NUCLEAR
REGULATORY TRANSCRIPTION PROTEINS
5. CELL CYCLE REGULATORY
PROTEINS- CYCLINS AND CYCLIN
DEPENDENT KINASES(CDKs).
MUTATIONS IN THESE PROTEINS
ARE MOST IMPORTANT GROWTH
PROMOTING SIGNALS IN
CANCERS
SIGNAL TRANSDUCTION- NUCLEAR
REGULATORY TRANSCRIPTION PROTEINS
EXAMPLES- OVEREXPRESSION OF
CYCLIN-D IN CARCINOMA
BREAST,LIVER,MANTLE CELL
LYMPHOMA,
AMPLIFICATION OF CDK4 IN
MLIGNANT MELANOMA
GLIOBLASTOMAS AND SARCOMAS.
11.REFRACTORINESS TO
GROWTH INHIBITION
GROWTH SUPRESSING
ANTIONCOGENES. MUTATED
ANTIONCOGENES BEHAVE
LIKE GROWTH PROMOTING
ONCOGENES.
11.REFRACTORINESS TO
GROWTH INHIBITION
MAJOR ANTIONCOGENES
IMPLICATED IN HUMAN
CANCER ARE ARE
1.RB GENE-NUCLEAR
TRANSCRIPTION GENE
PRESENT IN EVERY HUMAN
CELL.
11.REFRACTORINESS TO
GROWTH INHIBITION
MUTANT FORM OF RB GENE
PROMOTE CELL CYCLE –
RETINOBLASTOMA.
11.REFRACTORINESS TO
GROWTH INHIBITION
SPORADIC CASES OF
RETINOBLASTOMA- MUTATION
OF BOTH ALLELS IN RETINAL
CELLS OCCUR AFTER BIRTH
11.REFRACTORINESS TO
GROWTH INHIBITION
IN INHERITED CASES ALL
SOMATIC CELLS INHERIT ONE
MUTANT RB GENE FROM A
CARRIER PARENT, WHILE OTHER
ALLELE GETS MUTATED
LATER(TWO HIT HYPOTHESIS OF
KNUDSON).
11.REFRACTORINESS TO
GROWTH INHIBITION
MUTANT RB GENE IN
OSTEOSARCOMA,CARCINOMA
BREAST, COLON ,LUNGS
II .REFRACTERINESS TO GROWTH
INHIBITION-GROWTH SUPPRESSING
ANTIONCOGENES-
2.TP53 GENE –A GROWTH
SUPPRESSOR ANTIONCOGENE.
TWO MAJOR FUNCTIONS OF TP53
ARE
a.BLOCKING MITOTIC ACTIVITY
b.PROMOTING APOPTOSIS.
II .RFRACTERINESS TO GROWTH INHIBITIONGROWTH SUPPRESSING ANTIONCOGENES-
ACTS TOGETHER WITH RB
GENE IDENTIFIES CELLS WITH
DAMAGED DNA,DIRECTS SUCH
CELLS TO APOPTOSIS BY
ACTIVATING APOPTOSIS
INDUCING BAX GENE.
GROWTH SUPPRESSING
ANTIONCOGENES
TP53 IS CALLED THE
PROTECTOR OF GENOME.
MUTATED FORM OF TP53 ACT
LIKE A ONCOGENE
GROWTH SUPPRESSING
ANTIONCOGENES
3.TRANSFORMING GROWTH
FACTOR BETA. – ACT ON CELL
CYCLE –INHIBITS CELL
PROLIFERATION.
MUTATED FORM PERMITS CELL
PROLIFERATION-CARCINOMA
COLON,PANCREAS, STOMACH
GROWTH SUPPRESSING
ANTIONCOGENES
4. ADENOMATOUS POLYPOSIS
COLI (APC) GENE -INHIBITS
MITOSIS-THROUGH
CYTOPLASMIC PROTEIN - BETA
CATENIN WHICH BLOCKS THE
SIGNAL TO THE NUCLEUS.
GROWTH SUPPRESSING
ANTIONCOGENES
IN COLONIC CANCER APC GENE
IS LOST, THUS THE CANCER
CELLS CONTINUE TO UNDERGO
MITOSIS WITHOUT THE
INHIBITORY INFLUENCE OF BETA
CATENIN
GROWTH SUPPRESSOR
ONCOGENES
5 .OTHER ANTIONCOGENES
WILMS’ TUMOUR GENE-(WT)NORMALLY INHIBITS
PROLIFERATION OF CELLS IN
EMBRYONIC KIDNEY.MUTATED
WT GENES(WT1 AND 2) ARE SEEN
IN HEREDITORY WILMS’ TUMOUR.
GROWTH SUPPRESSOR
ONCOGENES
NEUROFIBROMA GENE(NF)PREVENT PROLIFERATION OF
SCHWANN CELLS.
2 MUTANT FORMS - NF1 AND NF2PROMOTE SCHWANN CELL
PROLIFERATION.
GROWTH SUPPRESSOR
ONCOGENES
BRCA 1 AND BRCA2- BREAST
CANCER SUSCEPTIBILITY GENES
–MUTATED FORMS ARE SEEN IN
INHERITED BREAST CANCER
111.ESCAPING CELL DEATH BY
APOPTOSIS
GENES REGULATING
APOPTOSIS AND CANCER.
TUMOUR GROWTH IS
PROMOTED BY ESCAPING
APOPTOSIS
111.ESCAPING CELL DEATH BY
APOPTOSIS
APOPTOSIS IS GUIDED BY CELL
DEATH RECEPTOR- CD95
RESULTING IN DNA DAMAGE
INVOLVING PROAPOPTOTIC
FACTORS (BAD,BAX AND BID
TP53)AND APOPTOSIS
INHIBITORS (BCL2,BCL-X)
GROWTH SUPPRESSOR
ANTIONCOGENES
CELL DEATH RECEPTOR CD95
ARE DEPLETED(APOPTOSIS
INHIBITION)
IN HEPATOCELLULAR
CARCINOMA.-GROWTH
CONTINUES UNCHECKED.
IV-AVOIDING CELLULAR AGINGTELOMERES AND TELOMERASE IN
CANCER
TELOMERES ARE THE TERMINAL
TIPS OF THE CHROMOSOMES.
WITH EACH MITOSIS THERE IS
PROGRESSIVE SHORTENING OF
TELOMERES.
IV-AVOIDING CELLULAR AGINGTELOMERES AND TELOMERASE IN
CANCER
TELOMERASE IS THE RNA
ENZYME
THAT HELPS IN REPAIRING DNA
DAMAGE AND MAITAINS NORMAL
TELOMERE LENGTH.
IV-AVOIDING CELLULAR AGINGTELOMERES AND TELOMERASE IN
CANCER
AFTER 60- 70 MITOSIS
TELOMERES ARE LOST IN
NORMAL CELLS AND THE
CELLS CEASE TO UNDERGO
MITOSIS.
IV- AVOIDING CELLULAR AGINGTELOMERES AND TELOMERASE IN
CANCER
UPREGULATION OF
TELOMERASE ENZYME
MAINTAINS TELOMERE LENGTH
IN CANCER CELLS.THUS CANCER
CELLS AVOID AGING.
V.INVASION ,METASTASIS:
CANCER DISSEMINATION
BY PRODUCING ENZYMES WHICH
DIGEST BASEMENT MEMBRANE AND
CONNECTIVE TISSUE MATRIXINVADE LOCALLY ENTER BLOOD
VESSELS AND LYMPHATICS TO
DISSEMINATE.
VI. DNA DAMAGE AND REPAIR
SYSTEM
MINOR DAMAGE OCCUR DURING
NORMAL MITOSIS WHICH IS
REPAIRED BEFORE MITOSIS IS
COMPLETED.
EXOGENOUS FACTORS LIKE
RADIATION CHEMICAL
CARCINOGENS,VIRUSES CAUSE
MUTATIONAL DAMAGE TO
DIVIDING CELLS.
VI. DNA DAMAGE AND REPAIR
SYSTEM
TP53 IS HELD RESPONSIBLE
FOR DETECTION AND REPAIR
OF DNA DAMAGE.
VI. DNA DAMAGE AND REPAIR
SYSTEM
IF DNA REPAIR IS
DEFECTIVE,DEFECT IN DNA IS
PASSED ON TO THE NEXT
PROGENY OF CELLS AND
CANCER RESULTS
VI. DNA DAMAGE AND REPAIR
SYSTEM
1 .ATAXIA TELANGIECTASIA –
MULTIPLE CANCERS WITH
CEREBELLAR
DEGENERATION,IMMUNOLOGIC
DERANGEMENTS,OCULOCUTANE
OUS MANIFESTATIONS
VI. DNA DAMAGE AND REPAIR
SYSTEM
2 .XERODERMA PIGMENTOSA
SKIN AND TISSUE COVERING
THE EYE ARE EXTREMELY
SENSITIVE TO ULTRAVIOLET
LIGHT. SYMPTOMS: SUNBURN
THAT DOES NOT HEAL.
VI. DNA DAMAGE AND REPAIR
SYSTEM
3. BLOOM SYNDROME TELANGIECTASES AND
PHOTOSENSITIVITY, GROWTH
DEFICIENCY OF PRENATAL ONSET,
VARIABLE DEGREES OF
IMMUNODEFICIENCY, AND
INCREASED SUSCEPTIBILITY TO
NEOPLASMS OF MANY SITES AND
TYPES. - LEUKAEMIAS
VI. DNA DAMAGE AND REPAIR
SYSTEM
4. HEREDITORY BREAST CANCER
PATIENTS HAVING BRCA1 AND
BRCA2 GENES. CARRYING
INHERITED DEFECTS IN DNA
REPAIR MECHANISM.
VII.CONTINUED PERFUSION OF
CANCER: CANCER ANGIOGENESIS
PROMOTERS OF TUMOUR
ANGIOGENESIS –
VEGF(FROM PARENCHYMAL
TUMOUR CELLS),AND
BASIC FIBROBLAST GROWTH
FACTER(b FGF )
VII. CONTINUED PERFUSION OF
CANCER: CANCER ANGIOGENESIS
ANTIANGIOGENESIS
FACTORS
THROMBOSPONDIN1
(PRODUCED BY ENDOTHELIAL
CELLS AND TUMOUR CELLS)
VII. CONTINUED PERFUSION OF
CANCER: CANCER ANGIOGENESIS
ANGIOSTATIN, ENDOSTATIN AND
VASCULOSTATIN-
MUTATED TP53 REMOVES
ANTIONCOANGIOGENIC ROLE OF
THROMBOSPONDIN
VIII .CANCER PROGRESSION,HETEROGENEITY:CLONAL AGGRESSIVENESS
WITH PASSAGE OF TIME
CANCER BECOMES MORE
AGGRESSIVE .
THIS PROPERTY IS CALLED
TUMOUR PROGRESSION.
VIII .CANCER PROGRESSION,HETEROGENEITY:CLONAL AGGRESSIVENESS
PARAMETERS OF CANCER
PROGRESSION AREINCREASE IN SIZE OF THE
TUMOUR,HIGHER HISTOLOGIC GRADE
(POORER DIFFERENTIATION,AND
GREATER ANAPLASIA),AREAS OF
TUMOUR NECROSIS,INVASIVENESS
AND DISTANT METASTASIS.
VIII- CANCER PROGRESSION,HETEROGENEITY:CLONAL AGGRESSIVENESS
WITH PASSAGE OF TIME CANCER
CELLS ACQUIRE MORE AND
MORE HETEROGENIETY (MORE
AND MORE MUTATIONS),MORE
AGGRESSIVE CLONES OF
CANCER CELLS EMERGE.
VIII- CANCER PROGRESSION,HETEROGENEITY:CLONAL AGGRESSIVENESS
DEVELOP TENDENCY TO
INVADE,METASTASISE AND
BECOME REFRACTERY TO
HORMONAL INFLUENCES.
ACTIVATION AND INACTIVATION OF CANCER
ASSOCIATED GENES IN CELL CYCLE
MOLECULAR BASIS OF
CANCER