This document discusses neoplasia and the molecular basis of cancer. It covers the clinical effects and spread of cancer, including tumor-host relationships and pathological diagnosis. Cancer causes local and systemic effects on the host through fever, weight loss, endocrine/neurologic/hematologic syndromes, and more. Cancer spreads locally through direct extension or metastatically through the blood or lymphatic system. The molecular basis of cancer involves genetic mutations in oncogenes and tumor suppressor genes that deregulate cell growth, proliferation, and apoptosis. Important oncogenes and tumor suppressors are described.

1. NEOPLASIA
Clinical effects and spread of cancer/
Molecular basis of cancer
Dr. S. Parasuraman
Faculty of Pharmacy, AIMST University

2. Clinical effects and spread of cancer
• Management of neoplasia is based on
– Tumour-host inter-relationship
– Laboratory/ pathological diagnosis of cancer
• Tumour-host inter-relationship depends upon host response against
tumour and effect of tumour on host.
• Laboratory/ pathological diagnosis of cancer mainly focus on histological
and cytochemistry analysis

3. Clinical effects of cancer
Tumour-host inter-relationship
• Immune system can recognize tumour cells as ‘non-self’
and destroy them.
• Immune surveillance exists is substantiated by increased
frequency of cancers in immunodeficient host e.g. AIDS
patients, post-transplant lymphoproliferative disease.
• Tumour can produce ill-effects and this effect may be
local or generalised and more widespread. Local effects
depends on size/ location (local effects: compression,
mechanical obstruction, tissue destruction, infarction,
ulceration, haemorrhage).

4. Clinical effects of cancer
Tumour-host inter-relationship
• Systemic effect of cancer on the host
– Fever:
• Most common in Hodgkin’s disease, renal cell carcinoma and osteogenic
sarcoma
• Tumour cell themselves release pyrogens/ inflammatory cells in the tumor
stroma, can produce interleukin-1 or TNF
– Anorexia and weight loss
• Paraneoplastic syndrome of anorexia, weight loss and cachexia is very
common in patients with cancer
– Endocrine syndromes
• Cushing syndrome
• Inappropriate antidiuresis
• Hypercalcemia
• Hypoglycemia

5. Clinical effects of cancer
Tumour-host inter-relationship
• Systemic effect of cancer on the host
– Neurologic syndromes
• Spinal cord: Subacute motor neuropathy
• Peripheral nerves: Sensorimotor peripheral neuropathy
– Skeletal muscle
• Dermatomyositis or polymyositis (5-7 fold higher than normal person)
– Hematologic syndromes
• Erythrocytosis (particularly renal cell carcinoma, hepatocellular carcinoma,
cerebellar hemangioblastoma); Anemiab (normocytic and normochromic
anemia); leukocytes and platelets
– Malabsorption
– Renal syndromes: Nephrotic syndrome (consequence of renal vein thrombosis
or amyloidosis)
– Cutaneous syndromes (pigmented lesions and keratoses)

6. Clinical effects of cancer
Pathological diagnosis of cancer
– Histological methods
– Cytological methods
– Histochemistry and cytochemistry
– Immunohistochemistry
– Electron microscopy
– Tumour marker
– Other modern aids
• Flow cytometry
• Molecular diagnostic techniques
• DNA microarray analysis of tumour

7. Spread of cancer
Primary cancer (site of first cancer
growth)
Secondary cancer/ metastasis (spread
form primary cancer)
?
Direct extension (local spread)
Metastatic spread (through the blood
circulation, lymphatic system )

8. Spread of cancer
• Direct extension (local spread)
– Grows directly into nearby body tissues
Benign  Dysplasia  In-situ
Benign  Dysplasia
nearby tissues
 In-situ  Invasive  spread into
– E.g. Peritoneal carcinomatosis (metastatic ovarian carcinoma)

9. Spread of cancer
• Metastatic spread:
– Transfer of malignant cells from
one site to another through
• Hematogenous metastases
• Lymphatic metastases
Stage I: Early disease (tumour confined)
Stage II: tumour spread to movable ipsilateral
axillary nodes
Stage III: Locally advanced disease; involvement
of ipsilateral mammary lymp nodes
Stage IV: Advanced (metastatic) disease

10. Molecular basis of cancer
Cancer Cell Do Not Grow Faster Than Normal Cells
Rather, Their Growth is Just Uncontrolled

11. Molecular basis of cancer
• Cancer is genetic disease
– Non lethal Genetic damage is heart of
carcinogenisis
– Somatic mutation/in genes/ inherited in
germline of persons leads to unregulated
growth of cancer cells.
– Most of cancers results form mutations in
somatic cells
– Some cancer are caused by mutations in
germline cells
– Mutations (by environmental mutagen or as
consequence of normal cellular metabolism or
by spontaneous errors in DNA replication and
repair) in genes results in altered proteins
• During cell division
• External agents
• Random event

12. Molecular pathogenesis of cancer
• Monoclonality of tumors:
– Most of the human cancer arise form a single clone of
cell by genetic transformation or mutation. E.g. multiple
myeloma (malignant of plasma cell) – due to inactivation
of two X-chromosomes in female for G6PD isoenzyme.
• Field theory of cancer:
– Limited number of cells only grow into cancer after
undergoing sequence of changes under the influence of
etiological agents.

13. Molecular pathogenesis of cancer
• Multi-step process of cancer growth:
Carcinogenesis is multistep process at both the phenotypic and
genetic level
– A malignant neoplasm has several phenotypic attributes such
as excessive growth, local invasiveness & distant metastasis
– These characteristics are acquired in a stepwise fashion called
tumor progression
• Genetic theory of cancer:
– Cell growth of normal as well as abnormal type is under
genetic control. In cancer, there are either genetic
abnormalities in the cell, or there are normal genes with
abnormal expression.

14. Molecular basis of cancer
• Genetic regulations of normal
mitosis:
– In normal cell growth has 4
regulatory genes
– Proto-oncogenes are growthpromoting genes (they encode for
cell proliferation pathway)
– Anti-oncogenes are growthinhibiting or growth suppressor
genets
– Apoptosis regulatory genes –
control the programmed cell
death
– DNA repair gene – normal gene
regulate the repair of DNA
damage during mitosis
• In Cancer:
• Fours classes of normal
regulatory genes are the
targets of genetic damage
– Activation
promoting
of
growthoncogenes
(PDGF)
– Inactivation of cancer
suppressor genes (RB gene,
NF-1 gene, p53 gene, WT-1
gene)
– Abnormalities
apoptosis
regulatory genes (BCL-2
gene, p53 gene)
– Failure of DNA repair gene

15. Molecular basis of cancer
Proto-oncogenes
may be converted to Oncogenes
by 3 mechanisms
1. Point mutation
2. Chromosomal rearrangements
3. Gene amplification

16. Chromosomal changes in the genome of cancer cells
Deletion
Terminal
Deletion
Reciprocal
translocation
Duplication
Insertion
Inversion
Ring
Chromosome
Robertsonian
Translocation
Isochromosomes
http://www.tokyo-med.ac.jp/genet/cai-e.htm

17. Nucleotide changes in the genome of cancer cells
Nucleotide
Deletions
Nucleotide
Insertions
Nucleotide
Substitutions
http://www.tokyo-med.ac.jp/genet/cai-e.htm

18. Important Oncogenes
Type
Proto-oncogene
Mechanism
Associated H. tumour
GROWTH FACTOR
PDGF-β
TGF-α
SIS
RAS
Overexpression
Overexpression
Gliomas, sarcoma
Carcinomas, astrocytoma
RECEPTORS FOR
GROWTH FACTORS
EGF receptors
RET receptor
ERB B1(HER 1)
RET
Overexpression
Point mutation
Squamous cell carcinoma lung
NUCLEAR
TRANSCRIPTION
FACTORS
C-MYC
N-MYC
MYC
MYC
Translocation
Amplification
Burkitt’s lymphoma
CELL CYCLE
REGULATORY
PROTEINS
CDKs
CDK4
Amplification
Glioblastoma, melanoma,
sarcomas
medullary Ca thyroid
Neuroblastoma, small cell Ca
lung

19. Important Tumour-suppressor anti-oncogenes
Type
Location
Associated H. tumour
RB
Nucleus (13q)
Retinoblastoma,
osteosarcoma
p53 (TP53)
Nucleus (17p)
Most human cancers,
common in Ca lung, head
and neck, colon, breast
TGF–β and its receptor
Extracellular
Ca pancreas, colon, stomach
APC and β-catenin
proteins
Nucleus and cytosol
Ca colon
Nucleus (BRCA1 17q21)
Nucleus (BRCA2 13q12-13)
Nucleus (3p)
Nucleus (11p)
Plasma membrane
Ca breast, ovary
Ca breast, ovary
Renal cell carcinoma
Wilms’ tumour
Neurofibromatosis
Others
BRCA 1
BRCA 2
VHL
WT 1 and 2
NF 1 and 2

20. Molecular basis of cancer

21. Major properties of cancer in terms of molecular carcinogenesis

22. DNA Loss in cancer cells

23. Clara_Jacobi-Tumor
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24. Cushing syndrome
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25. Dermatomyositis
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26. cerebellar hemangioblastoma
hemangioblastoma
hemangioblastoma
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Erythrocytosis
renal cell carcinoma
renal cell carcinoma

27. Renal vein thrombosis
Amyloid deposits in renal cells
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28. Cutaneous syndromes
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