Hallmarks of cancer & its clinical aspects.ppt

Hallmarks of cancer

1. Hallmarks of cancer and it’s
clinical aspects
Division of Molecular Medicine
01-09-2021

2. Introduction
Carcinogenesis is a MULTISTEP PROCESS !

3. 1.Sustaining proliferative signaling
•Proto-oncogenes: Normal genes whose products
promote cell growth.
•Oncogenes: are mutant versions of proto-oncogenes
that function autonomously without normal signals.
•Oncoprotein: a protein encoded by an oncogene that
drives increased cell proliferation through one of
several mechanisms.

4. They include :
•Growth factors
•Cell surface receptors
•Signal transduction proteins
•Nuclear transcription factors
•Cell cycle proteins

5. Oncogenes coding Growth Factors
•Normal Cell growth is stimulated by GF
•Platelet derived growth factor (PDGF) -glioblastomas
•Fibroblast growth factor(FGF)-stomach CA & melanoma
•Transforming Growth Factor (TGF-)in sarcomas
Oncogenes coding Growth Factor Receptors
•Amplification of EGF receptor family genes such as HER2 in
breast cancer
Oncogenes in Signal Transduction
•GTP-binding proteins
•Fusion of portions of the ABL tyrosine kinase gene and the
BCR protein gene, creating a BCR-ABL fusion gene encoding
a constitutively active tyrosine kinase.

6. Nuclear Transcription Factors
•DNA transcription regulated by genes-MYC, JUN,FOS.
•In normal : MYC protein + DNA Activation of Cyclin
DependantKinases ( CDK’s) initiation of cell cycle 
MYC
•MYC mutation sustained activation
•Ex:Dysregulationof MYC -Burkitt’s lymphoma (t8:14)
Cell cycle regulators
•Cyclins & Cyclin Dependent –Kinases regulate Cell Cycle
phases.
Mutations in genes encoding cyclins, CDKs, and CDK inhibitors result in uncontrolled cell
cycle progression -melanomas and brain, lung, and pancreatic cancers.

7. 2. Insensitivity to Growth Inhibitory Signals:
Tumor Suppressor Genes
•Whereas oncogenes encode proteins that promote cell
growth, the products of tumor suppressor genes apply
brakes to cell proliferation.
•Disruption of such genes renders cells refractory to
growth inhibition and mimics the growth-promoting
effects of oncogenes.
•RB -Governor of cell cycle
•TP53 -Guardian of the Genome

8. 3. Altered Cellular Metabolism
•Even in the presence of ample oxygen, cancer cells demonstrate a distinctive form of
cellular metabolism characterized by high levels of glucose uptake and increased
conversion of glucose to lactose (fermentation) via the glycolytic pathway.
•This phenomenon, called the Warburg effect aka aerobic glycolysis.
•Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates
that are needed for the synthesis of cellular components, whereas mitochondrial
oxidative phosphorylation does not.

9. 4. Evasion of Cell Death(Apoptosis)
Evasion of cell death by cancers mainly involves acquired
abnormalities that interfere with the intrinsic (mitochondrial)
pathway of apoptosis.
• The MC abnormalities involve loss of p53 function,
either by way of TP53 mutations or overexpression of the p53
inhibitor MDM2.
• Other cancers evade cell death by overexpressing anti-apoptotic
members of the BCL2 family, such as BCL2, BCL-XL, and MCL1,
which protect cells from the action of BAX and BAK,
the pro-apoptotic members of the BCL2 family.
• In follicular B-cell lymphomas, BCL2 levels are high because of a
(14;18) translocation that fuses the BCL2 gene with regulatory
elements of the immunoglobulin heavy chain gene.
• Inhibitors of MDM2 (which activate p53) and inhibitors of
BCL2 family members induce the death of cancer cells by
stimulating the intrinsic pathway of apoptosis and are being
developed as therapeutic agents.

10. Multistep Carcinogenesis :

11. 5. Limitless Replicative Potential (Immortality)
•Tumor cells, unlike normal cells, are capable of limitless replication.
•In normal cells, which lack expression of telomerase, the shortened telomeres generated by
cell division eventually activate cell cycle checkpoints, leading to senescence and placing a
limit on the number of divisions a cell may undergo.
•In cells that have disabled checkpoints, DNA repair pathways are inappropriately activated
by shortened telomeres, leading to massive chromosomal instability and mitotic crisis.
•Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving
immortality.

12. 6. Sustained Angiogenesis
•Vascularization of tumors is essential for their growth and is controlled by
the balance between angiogenic and antiangiogenic factors that are
produced by tumor and stromal cells.
•Hypoxia triggers angiogenesis through the actions of HIF-1α on the
transcription of the proangiogenic factor VEGF.
•Many other factors regulate angiogenesis; for example, p53 induces
synthesis of the angiogenesis inhibitor thombospondin-1, while RAS, MYC,
and MAPK signaling all upregulate VEGF expression and stimulate
angiogenesis.
•VEGF inhibitors are used to treat a number of advanced cancers and prolong
the clinical course, but are not curative.

13. 7. Invasion and Metastasis

14. The metastatic cascade: The sequential steps
involved in the hematogenous spread of a tumor
Loosening of cell–cell contacts, degradation of ECM,
attachment to novel ECM components, and migration of
tumor cells.
• Cell–cell contacts are lost by the inactivation of E-cadherin
• Basement membrane and interstitial matrix degradation is
mediated by proteolytic enzymes secreted by tumor cells and
stromal cells, such as MMPs and cathepsins.
• Proteolytic enzymes also release growth factors sequestered
in the ECM and generate chemotactic and angiogenic
fragmentsfromcleavage of ECM glycoproteins.
• The metastatic site of many tumors can be predicted by the
location of the primary tumor. Many tumors arrest in the first
capillary bed they encounter (lung and liver, most
commonly).
• Some tumors show organ tropism, probably due to
activation of adhesion or chemokine receptors whose ligands
areexpressedby endothelial cells at the metastatic site.

15. 8. Evasion of Immune Surveillance
Cross-presentation of tumor antigens and induction
of CD8+ cytotoxic T cell antitumor response.

16. Blockade of the CTLA4 surface molecule with an inhibitor antibody allows cytolytic CD8+ T cells (CTLs) to engage B7
family coreceptors, leading to T cell activation.
Blockade of PD-1 receptor or PD-1 ligand by inhibitory antibodies abrogates inhibitory signals transmitted by PD-1, again
leading to activation of CTLs.

17. 9. Genomic Instability as an Enabler of Malignancy
•Individuals with inherited mutations of genes involved in DNA repair systems are at greatly
increased risk for the development of cancer.
•Patients with HNPCC syndrome have defects in the mismatch repair system, leading to
development of carcinomas of the colon. These patients’ genomes show microsatellite instability
(MSI), characterized by changes in length of short tandem repeating sequences throughout the
genome.
•Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair pathway.
They are at increased risk for the development of skin cancers in sites exposed to sunlight
because of an inability to repair pyrimidine dimers induced by UV light.
•Syndromes involving defects in the homologous recombination DNA repair system constitute a
group of disorders—Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia—that are
characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation. BRCA1 and
BRCA2, which are mutated in familial breast cancers, also are involved in homologous DNA
repair.
•Mutations incurred in lymphocytes expressing gene products that induce genomic instability
(RAG1, RAG2, AID) are important in the pathogenesis of lymphoid neoplasms.

18. 10. Tumor-Promoting Inflammation as an Enabler
of Malignancy
•Release of factors that promote proliferation
•Removal of growth suppressors
•Enhanced resistance to cell death
•Angiogenesis
•Invasion and metastasis
•Evasion of immune destruction

19. Clinical Aspects of Neoplasia
•Location of tumor is of importance
1-Mass effect by pressing on vital areas Ex: airway, intestine , BV,
brain, nerveobstruction, infarction , paralysis…etc
2-Local destruction of epithelial surface or BV ulceration bleeding ,
infection
3-Hormonal activity
4-Cancer Cachexia :Wasting syndrome characterized by anorexia ,
loss of body fat & weight, with marked weakness, anemia & fever.
•Reduced food intake but high metabolic rate.
•Possibly due to release of cytokinesby tumor cells & macrophages.

20. 5 -Paraneoplastic Syndrome :
•Systemic symptoms that can’t be explained by effects of local or
distant spread of tumor or hormones appropriate to tumor
tissue.
•Due to ectopic production of hormones or other factors
•They may precede the tumor or mimic metastases
•They occur in about 10%-15%of malignant tumors.

22. Grading & Staging of Tumors :
Must be documented for all malignant tumours :
•To quantify the aggressiveness of tumor
•To outline mode of therapy
•To compare different modes of therapy
•To give an approximate prognosis

23. Grade of tumor: Based on level of differention:
This indicates the degree of resemblance of tumor cells
to cell of origin and isalwaysbased on microscopic
criteria.
•Grade I : Well differentiated tumor
•Grade II :Moderately differentiated tumor
•Grade III : Poorly differentiated tumor
•Grade IV : Anaplastic tumor

24. Stage of Tumor :
•This indicates the extent of spreadof the tumor.
•Clinical ,investigative procedures and pathological
appearance of tumor have to be used to assess it.
•It depends on :
*Size of tumor
* Regional lymph node involvement
* Metastases to distant organs

25. TNM Staging System :
•T: Size and extent of primary tumor(1-4)
•N: Presence and extent of lymph node involvement ( 0-3)
•M: Presence or absence of distant metastasis ( X0-1)
e.g.T1,N1, M0
•Staging is more important than grading because it
affects treatment

26. CANCER DIAGNOSIS
•General Outline :
oHistory & clinical examination
oRadiographic techniques
i-X ray
ii-CT scan
iii-MRI
iv-Ultrasound
oLaboratory tests : general & specialized

27. 1-Cytological methods :
•Study of cells :
-Smear
-FNA, Brush, Fluid tapping…etc
2-Histological methods :
•Biopsy of tissue:Needle & core biopsy , Endoscopic
Biopsy, or open surgical biopsy
•Frozen Section (Rapid technique)
•Paraffin Section ( 36-48 hrs. or longer )
•H&E, Special histochemical stains e.g.
( PAS, CONGO RED, PERL’sstains) or by
IMMUNOHISTOCHEMICALMethods

28. •3-Immunocytochemistry
•Staining by use of monoclonal AB directed
against various components in cell may help in
diagnosis of undifferentiated cancers or help
in identifying source of a metastatic tumor.
e.g.
•CytokeratinCarcinoma
Common leukocyte antigenLymphoma
S 100Neural tissue, melanocytic lesions
Desmin, Vimentin Sarcoma

29. •4-Electron microscopy : For recognition of
desmosomes , or neurosecretory granules….etc.
5-Flow Cytometry :
•For measuring DNA content , detecting
diploid versus aneuploid tumors….etc.
•Correlates with rate of growth & prognosis
•Useful in the diagnosis & classification of
Lymphoma & Leukemia

30. 2-Biochemical Assays :
•Used to identify tumor associated enzymes,
hormones , antigens … etc
•These are useful as markers for diagnosis of a
tumor OR for assessing the progress of a
known tumor
•Their uses are to :
I -Confirm diagnosis.
II -Determine the response to treatment .
III -Detect early relapse.
•Present in serum or urine.
•Many are present in normal & tumor tissue, so they are not very specific but their level is
important.

31. Types of Tumor Markers
1-Hormones:
•Human Chorionic Gonadotrophic Hormone (HCG): Elevated levels are seen in Pregnancy
& Gestational Trophoblastic Disease
•Calcitoninuseful in diagnosis of some thyroid carcinomas
2-Oncofetal Antigens :Carcinoembryonic Antigen ( CEA ) :in fetal tissue & some malignancies –
Colorectal CA & Pancreatic CA
Alpha Fetoprotein (AFP): Cirrhosis, HCC
3-Isoenzymes :Prostatic Acid Phosphatase ( PAP )levels seen in Metastatic prostatic CA
Useful in : * Staging prostatic CA
* Assessment of prognosis
* Response to therapy.
4-Specific Proteins:Immunoglobulinssecreted in Multiple Myeloma
•Prostate -specific antigen ( PSA ) :Present in epithelium of prostatic ducts.
* Prostatic hyperplasia &
* in Prostatic CA
* Level correlates with Stage of CA
•5-Several mucins
MUC-1 in breast CA
CA-125 in ovarian CA
CA-19-9 in pancreatic & hepatobiliary CA

32. 3-Molecular Diagnosis :
•Methods used include :
–PCR (Polymerase Chain Reaction)
–FISH (Fluorescent In Situ Hybridization)
•Used to detect gene rearrangement, translocations, amplifications…etc
–BCR-ABLChronic Myeloid Leukemia
–Monoclonal proliferationof B or T cells
–13q 14deletion in Retinoblastoma….
•For prognosis : gene amplification
–HER-2 NEUin breast carcinoma
–N-MYCin neuroblastoma
•Detection of residual disease in chronic myeloid leukemia (BCR-ABL)
•Detection of genes of hereditarycancer e.g BRCA-1in breast cancer

33. THANK YOU