Biology of cancer

Growth Disturbances
Atrophy
Decrease in size of cells causing corresponding decrease in the tissue mass
Physiologic: Uterus following parturition
Pathologic : Udescended testes (pressure atrophy)
Hypertrophy
It is enlargement in the individual cell size, causing corresponding increase in the tissue mass
-Physiological : myometrium of the gravid uterus
-Pathological : left ventricle in systemic hypertension
Hyperplasia
An increase in organ size or tissue mass caused by an increase in the number of constituent
cells
•Occurs only in cells capable of mitotic division
•May occur concurrently with hypertrophy
Hyperplasia can be physiologic or pathologic
•Hormonal:
–Mammary gland hyperplasia
•Compensatory:
–hyperplasia of the contralateral kidney
•Regenerative:
–hyperplasia of the liver or bone marrow

METAPLASIA
Change of one type of differentiated tissue to another type of same class of tissue
Causes:
- Chronic irritation.
- Deficiency of certain factors as Vit. A
Types:
(1) Epithelial
(2) Connective tissue Formation of bone in fibrous tissue : in
traumatic myositis ossificans
(3) Mesothelial flat mesothelium into cubical or columnar cells
(4) Tumor in some tumors as squamous metaplsia
(5) Mucoid in breast carcinoma
Growth Disturbances ,,cont..
MECHANISM OF METAPLASIA
•Metaplasia does not results in the phenotype of a differentiated cell type
•It is the result of reprogrammed stem cells that are known to exist in normal tissue or of
undifferentiated mesenchymal cells present in connective tissue
•In metaplastic changes , these precursor cells differentiated along a new pathway
•The differentiation of stem cells to a particular lineage is brought about by signals
generated by cytokines and growth factors

Growth Disturbances ,,cont..
DYSPLASIA
It is a disordered cellular proliferation
Characters of dysplastic cells:
-Pleomorphism (Variation in size and shape)
-Loss of polarity (orientation)
-Hyperchromatic nuclei ( deep basophilic staining)
-Occasional presence of mitosis
-Usually associated with chronic irritation
-Prognosis:
Although it is potentially reversible it is a premalignant lesion that can progress into cancer
SITES :
It is commonly encountered in :
•Cervix uteri and vagina
•Mucosa of respiratory tract
•Mucosa of the urinary bladder
•Mucosa of the gall bladder
•skin
•Oral mucosa
GRADING OF DYSPLASIA
Grade I dysplasia taking lower 1/3 of the thickness
of cells
Grade II dysplasia taking lower 2/3 of the thickness
of cells
Grade III dysplasia taking the whole thickness of
cells

Regulation of cell cycle
Stages of the normal cell cycle
There are two main phases in the cell cycle: Interphase and Mitotic Phase
Interphase
Phase 1, G1.
• This is a period of rapid growth. G1 is the longest stage of thencell cycle.
• During G1, a cell grows and carries out its normal cell functions.
• Most cells continue the cell cycle. However, some cells stop the cell cycle at the G1 stage.
Mature nerve cells in your brain remain in G1 and do not divide again. Synthetic phase, S.
The Cell replicates its nuclear DNA
• During the S stage, a cell grows and copies its DNA.
• Strands of chromatin are copied, so there are now two identical strands of DNA. This is
necessary because each new cell gets a copy of the genetic information.
• The new strands coil up and form chromosomes.
• A cell’s DNA is arranged as pairs. Each pair is called a duplicated chromosome.
• Two identical chromosomes called sister chromatids make up a duplicated chromosome.
• The sister chromatids are held together by a structure called a centromere.
Phase 2, G2,. It is the interval between the
• This is another period of growth and the final preparation for mitosis.
• A cell uses energy to copy DNA during the S stage.
• During G2, the cell stores energy that will be used during the mitotic phase of the cell cycle.

Mitotic Phase
Prophase:
• During the first phase of mitosis, called prophase, the copied chromatin coils together tightly.
• The coils form duplicated chromosomes that can be seen with a microscope.
• The nucleolus disappears and the nuclear membrane breaksdown.
• Structures called spindle fibers form in the cytoplasm.
Metaphase:
• The spindle fibers pull and push the duplicated chromosomesto the middle of the cell during metaphase.
• The chromosomes line up along the middle of the cell. This makes sure that each new cell will receive
one copy of each chromosome.
• Metaphase is the shortest phase in mitosis. It is an important phase because it makes the new cells the same.
Anaphase:
• In anaphase, the two sister chromatids separate from eachother and are pulled in opposite directions.
• Once they are separated, the chromatids are now two identical single-strandedchromosomes.
• As the single-stranded chromosomes move to opposite sides of the cell, the cell begins to get longer.
• Anaphase ends when the two sets of identical chromosomes reach opposite ends of the cell.
Telophase:
• During telophase, the spindle fibers that helped divide chromosomes begin to disappear.
• The chromosomes begin to uncoil.
• A nuclear membrane grows around each set of chromosomes at either end of the cell.
• Two new identical nuclei form.
cytokinesis
• In an animal cell, the cell membrane contracts, or squeezes together, around the middle of the cell.
• Fibers around the center of the cell pull together. This forms a crease, called a furrow, in the middle of
the cell. This furrow gets deeper and deeper until the cell membrane comes together and divides the cell.

Cyclins and cyclin-dependent kinases
(CDKs) are nuclear proteins
Cyclins
- They are a family of the proteins that undergo a cycle of synthesis and
degradation in each round of cell cycle,
- - Cell cycle regulating kinases are controlled by cyclins
- Cyclins have no enzymatic activity
- Cyclins have to bind to the kinases before the kinases can become active
- The kinases are therefore called cyclin dependent protein kinases or Cdks.
The molecular basis of cell-cycle regulation
Positive regulators for cell cycle
• Cyclins & cyclin-dependent kinases
Negative regulators for cell cycle.
• Cyclin-dependent kinase inhibitors (e.g. p15, p16, p21, p27)
•Tumor suppressor genes (e.g. p53, Rb, NF1,2, WT1 BRCA1, 2)
Regulation of cell cycle,,cont..

Cyclin-dependent kinases, CDKs
-They are a group of serine/ threonine protein kinase enzymes that are activated only
when bound to cyclins.
-They contribute in the regulation of cell cycle by phosphorylating Ser or Thr residues in
specific proteins such as RB protein.
- There are about six known types of CDKs (CDK1----6).
- The substrate specificity of CDKs is dependent on both cyclin and CDK bound together.
Cyclin-dependent kinase inhibitors
• They inhibit cyclin/CDK, thus, inhibit the progression through the cell cycle. Examples:
p15, p16, p21 (waf1/CIP), P27.
• p21 is a protein that binds to cyclin and CdK blocking entry into S phase.
• They are considered as TSGs, the inactivation of which(mutation or deletion) could
produce cancer
Tumor suppressor genes (TSG):
Tsg are genes that control the progression of cells into cell cycle for division.
•They prevent cells containing DNA mutations from entering cells cycle to divide.
Examples: p53, Rb (retinoblastoma), WT1 (Wilm’s tumor), APC
(adenomatous polyposiss coli), DCC (deleted in colorectal cancer),
NF1, NF2 (neurofibromatosis), MCC (mutated in colorectal cancer).
• The protein products of Rb and p53 genes delay the progression of the cell cycle under
normal condition.Therefore, they counteract the action of oncogenes.
• They are inhibited (mutated) in most cancers.

Retinoblastoma protein (pRb)
Retinoblastoma gene is the first TSG discovered and is located in 13q14.
pRb is a nuclear phosphoprotein (M.Wt 110KD) involved in negative regulation of cell cycle
progression as it, in its active form, delays the transition from G0/G1 to S phase of the cell
cycle.
In its active (hypophosphorylated state), pRb binds to and inhibits certain transcription factors
(e.g. E2F).
When non dividing cells are stimulated by growth factors or other mitogenic signals, CDKs
phosphorylate pRb (in late G1 phase).
This causes pRb to become in its inactive hyperphosphorylated form. Thus it releases the
transcription factors essential of cell proliferation and the cell cycle proceeds to the S phase.
Function of Retinoblastoma protein: Rbp
RB´s function: “a signal transducer connecting the cell cycle clock with the transcriptional
machinery”
RB inactivation may occur by four known Mechanisms:
(a) The RB gene is mutated (dashed line),causing release of its associated factors.
RB mutations have been detected in retinoblastoma and a small fraction of sporadic tumors.
(b) RB is sequestered by viral oncoproteins, preventing binding to other factors such as
humanpapillomavirus →E7and adenovirus → E1A
(c)Phosphorylation (P) of RB by CDK– cyclin complexes. This inactive hyperphosphorylated
form is essential of cell proliferation during cell-cycle
(d) RB is degraded by a proteolytic pathway during apoptosis.

p53 gene: It is located at chromosome 17P13.1. It is a TSG, its gene product is a nuclear phosphoprotein
(molecular mass 53 KDa) wild type, rapidly degraded in normal cells so its concentration is very low.In
response to DNA damage in G1 or G2 phase, p53 rises dramatically.
Most commonly mutated tumor suppressor gene associated with human cancers is p53 p53
protein has at least 3 major effects:
I- Acts as transcriptional activator (factor), regulating certain genes involved in cell cycle.
- It activates transcription of DNA repair proteins and cell cycle inhibitors (e.g. GADD45, P21, MDM2)
II- It acts as a G1 checkpoint control for DNA damage: If excess damage to DNA has occurred
(e.g. following UV irradiation), the activity of p53 increases resulting in inhibition of the cell
cycle ( expression of p21) and allowing time for DNA repair.
So if the cell cycle proceeds unchecked or if p53 is not functioning, DNA
damage will accumulate, mutations will occurs producing tumors and the
cell will be genetically less stable. Thus, p53 has been proposed to act as
(guardian of the genome).
Actually , if DNA damage is present, and the cell failed to repair, p53 triggers cell death (apoptosis).
III- p53 participates in the initiation of programmed cell death (apoptosis).
p53 hastens the cell death of potentially dangerous cells (e.g. those damaged by UV
irradiation) which have the potential to become malignant.
The role of p53 in stimulating apoptosis can be explained as follows:
p53 acts as transcriptional factor to up regulate BAX gene and down regulate bcl2 gene.
• BAX protein stimulate apoptosis while
• Bcl2 protein inhibits apoptosis
p53 (The guardian of the genome/ the molecular policeman)

DNA strucutre
• DNA is a polynucleotide; nucleotides are composed of a phosphate, a sugar, and a nitrogen-containing
base.
• The sugar in DNA is deoxyribose
• The four different bases in DNA are: adenine (A), thymine (T), guanine (G), and cytosine (C).
• Watson and Crick showed that DNA is a double helix in which A is paired with T &G is paired with C
• This is called complementary base pairing because a purine is always paired with a pyrimidine
• When the DNA double helix unwinds, it resembles a ladder.
• The sides of the ladder are the sugar-phosphate backbones, and the rungs of the ladder are the
complementary paired bases.
• The two DNA strands are anti-parallel – they run in opposite directions.
Chromosome Structure
■Chromosomes are thread-like or rod-like structures made of DNA nucleic acids and protein that carry
genetic information in the form of genes
■Each chromosomes has a short upper arm called the p arm (petit) and a longer lower arm called the q
arm. The central segment, joining the two arms, is called the centromere
■Chromosomes can be distinguished from one another by size, location of the centromere and the
pattern of dark and light bands
The Karyotype :
• Somatic cells are diploid, each contains 23 pair of chromosomes
• Of these 46 chromosomes 23 are paternal and 23 are maternal.
• The microscopic picture of the entire set of chromosomes of a cell is called the karyotype
• The normal male karyotype is 46, XY. The normal female karyotype is 46,XX.
• Karyotype is the complete set of chromosomes of an individual or a species. Chromosomes have different structures
(lengths and shapes) The process of studying of karyotypes is known as karyotyping

Chromosomal Abnormalities
• The correct number and structure of chromosomes is essential for normal body development and function
• These abnormalities could involve chromosome number or structure
• Excess or lack of genetic material cause problems.
• Polyploidy is the gain of whole sets of chromosomes, whereas aneuploidy is the gain or loss of individual chromosomes.
Polyploidy
• Fertilization of the ovum by more than one sperm (polyspermy) causes polyploidy
• Triploidy occurs when the ovum is fertilized by two sperms resulting in one complete extra set of chromosomes
Tetraploidy occurs when the ovum fertilized by three sperms resulting in two extra sets of chromosomes
• Polyploidy generally leads to early miscarriage, however some triploids can survive to the third trimester of pregnancy.
Aneuploidy
• Aneuploidy denotes a total number of chromosomes that is less or more than 46 (e.g. 45 or 47)
• It often results from non-disjunction or anaphase lagging.
• Non-disjunction is the failure of sister chromosomes or chromatids to separate during cell division.
• It may take place during any cell division but usually takes place during meiosis of the oocyte particularly in women
over the age 35.
• Non-disjunction and lagging may cause trisomy, monosomy or mosaicism.
TRISOMY
• Trisomy is presence of three copies of the same chromosomes in cells of the body.
• At the time of fertilization the ovum or sperm may contains two copies of the same chromosome.
• The resulting zygote contains three copies of that chromosome and so all cells of the body.
• Total chromosome number will be 47 instead 46.
• Trisomy can involve an autosome (13, 18 or 21) or a sex chromosome (X or Y)
MONOSOMY
• Monosomy results from loss of a copy of a chromosome that yields a total chromosomes number of 45 (e.g. 45,X).
• Autosomal monosomy is extremely uncommon and is more serious than trisomy often causing spontaneous
abortion.
• Sex chromosome monosomy is usually a monosomy X (XO) that causes Turner syndrome. Female patients are often
short, infantile with nonfunctioning ovaries, tubes and uterus

• Deletion: is the loss of a piece of a chromosome. Cri du Chat Syndrome
is an example
• Translocation : is an exchange of material between two chromosomes.
• Translocation Down syndrome is an example
• Inversion : is a rearrangement of the chromosome material in a reverse
order.
Affected persons are normal but offspring may suffer abnormalities
• Duplication: is the presence of an extra copy of a piece of a
chromosome. There is no loss of genetic material thus it is less harmful
than deletion
• Ring Chromosome Formation: results from deletion of the ends of a
chromosome followed by the fusion of both ends to form a circular
chromosome
• ISOCHROMOSOME formation: results from division of the centromere
transversely instead of longitudinally. Thus each daughter chromosome
has two identical arms and is deficient in one arm
Structural Chromosome Abnormalities Structural chromosome abnormalities result from
chromosome breakage at fragile sites followed by loss of part of a chromosome or abnormal
recombination of the chromosome.
They are of many types that include: Deletion ,Duplication ,Inversion , Translocation ,
Ring chromosome formation and Isochromosome formation

DNA damage and repair
DNA damage
I. Single-base alteration
1. Deamination of Cytosine to Uracil by Hydrolysis
2. Deamination of adenine to hypoxanthine by Hydrolysis
3. Depurination-by Hydrolysis: remove (A or G) is removed from deoxyribose sugar
4-Alkylation: Transfer of methyl or ethyl group to DNA bases
5-Base analogs: e.g. 5-bromouracil is an anolog of thymine and aminpurine is analog for adenine
II. Two-base alteration
1- UV light: induced thymine-thymine dimer (e.g.Xeroderma Pigmentosum )
2- Bifunctional alkylating agents: adding alkyle group in two different 7-N-guanine residues of DNA like nitrogen
mustard and sulfur mustard
III. Chain breaks
1. Ionizing radiation
2. Radioactive elements
3. Oxidative free radical formation: cause base-mispairing
IV. Cross-linkage
• Between bases in same or opposite strands
• B. Between DNA and protein molecules (eg, histones)

DNA repair
There are four mechanisms for DNA repairing based type of DNA damage.
 Base excision repair
• Removal of damaged base
• Creating a gap.
• Adding nucleotides then sealed by ligase.
 Nucleotide excision-repair
• Recognizing damaged nucleotides by a group of proteins & unwinding DNA containing defects.
• Removal of damaged base by endonuclease
• Base pairing new nucleotides by polymerase (δ/ε) then joined to the existing strands by DNA ligases.
 Mismatch repair
• Recognizing mismatched nucleotide
• Removing incorrect nucleotides
• DNA polymerase III & DNA ligase add correct nucleotides
 Doublestrand break repair
Ku protein and DNA-protein kinase bind DNA combine for:
• Approximation of two DNA strands
• Unwinding of DNA then
• Alignment and base pairing ligation
• Removal of extra ends by a DNA-PK-associated endo- or exonuclease

Neoplasia :
• New growth
•Uncontrolled cell division non responsive to growth controls
•Progressive, Purposeless, Pathologic, Proliferation of cells
Neoplasm :
• Abnormal mass of tissue
• Uncoordinated growth which exceed normal
• Persists after cessation of the stimuli
Tumor : Swelling
Oncology : The study of tumors or neoplasm
Cancer : Common term for all malignant tumors
Carcinogens : Chemical, physical & genetic DNAdamage Neoplasm
Neoplasia

Tissue of Origin Benign Malignant
Tumors Composed of One Parenchymal Cell Type
-Connective tissue and derivatives
• Fibrous tissue Fibroma Fibrosarcoma
• Adipose tissue Lipoma Liposarcoma
• Cartilage Chondroma Chondrosarcoma
• Bone Osteoma Osteogenic sarcoma
-Endothelial and related tissues
• Blood vessels Hemangioma Angiosarcoma
• Lymph vessels Lymphangioma Lymphangiosarcoma
• Synovium Synovial sarcoma
• Mesothelium Mesothelioma
• Brain coverings Meningioma Invasive meningioma
-Blood cells and related cells
• Hematopoietic cells Leukemias
• Lymphoid tissue Lymphomas
• Muscle :
I. Smooth Leiomyoma Leiomyosarcoma
II. Striated Rhabdomyoma Rhabdomyosarcoma
Classification of tumors

Biochemical Basis of Cancer
Definition and types of mutation
Mutagen: is a physical or chemical substance that cause mutations.
Mutagenesis: is the process of production of mutation. It may be spontaneous or induced.
Mutation: is a stable and permanent change in the DNA structure of a gene, which may be
expressed as a phenotypic change in the organism. It may occur in somatic cells (aren’t
passed to offspring), or, occur in gametes (ova & sperm) and be passed to offspring.
Mutations in DNA may be classified into two major types:
(1) Base substitution mutation (Transition or transversion)
(2) Frameshift mutations (Deletion or insertion)
Base Substitution Mutation
• Transition, in which one purine-pyrimidine base pair is substituted by another
(AT GC).
• Transversion, in which one purine-pyrimidine pair is transversed (CG GC).
Frameshift mutation
• Deletion or insertion of base pair resulted in change of reading frame.

1) Missense mutation
Base pair substitution results in substitution of a different amino acid (Ex: HbS in sickle cell
anemia).
2) Nonsense mutation
Base pair substitution results in a stop codon (shorter polypeptide i.e. truncated protein).
3) Neutral mutation
Base pair substitution results in substitution of an amino acid with similar chemical properties
(protein function is not altered).
4) Silent mutation
Base pair substitution results in the same amino acid. They may occur in a region that does not
code for a protein, or they may occur within a codon in a manner that does not alter the
final amino acid sequence
Types of mutations according to their impacts
on protein sequence:

A carcinogen is a substance known to cause cancer. Carcinogenic substances may be
inhaled, absorbed through the skin or ingested.
Carcinogenesis refers to the process by which a normal cell is transformed into a
malignant cell and repeatedly divides to become a cancer.
Carcinogens may be:
* Chemical substances
* Radiation (e.g. UV and X-ray)
* Biological agents (e.g. human papilloma virus, HBV and Epstein Bar viruses, EBV)
Carcinogenesis
Chemical carcinogens
1. Occupation hazards: Gasoline (Benzene), diesel exhausts and asbestos.
2. Diet contaminants: mycotoxins such as aflatoxin B1 and ochratoxin
3. Life style: smoking of tobacco cigarettes which contains benzo[α] pyrene which
metabolically oxidized in the cell and then binds to guanine on DNA producing
damage of the helix.
4. Drugs: base analogs (Fluoruracil) and alkylating agents (Cyclophophamide). Also,
some laboratory reagents like ethidium bromide which interchelate DNA molecule.
Nature of chemical carcinogens
1. Polycyclic aromatic hydrocarbon, e.g., benzo[α]pyrene.
2. Aromatic amines.
3. Nitrosamines.
4. Inorganic elements, e.g., As, Cd, Cr and Be.

Proto-oncogenes and oncogenes
• A proto-oncogene is a normal gene that can become an oncogene upon mutations. The
oncogene helps turn of a normal cell into a tumor cell when mutated due to
environmental factors.
• The proto-oncogenes work mainly in controlling the cell cycle and rate of cell division.
Types of proto-oncogenes:
1. Growth factors (GF): PDGF, FGF, EGF, TGFa, wnt, Neurotrophins, interleukins, CSF
2. Growth factors receptors (GFR): PDGFR, FGFR, EGFR, IGFR, HGFR, NGFR
3. Cytoplasmic protein kinases: involved in cell proliferation: ras, raf, src, abl, PKC
4. Nuclear transcription factors: fos, jun, myc , rel
5. Signaling molecules: Ras, vav, Tiam-1
6. Apoptosis regulator factors: bcl-2, Akt
Growth factors
Growth factors are naturally occurring molecules capable of stimulating cellular growth,
proliferation and cellular differentiation. Also, they are important for regulating a variety of
cellular processes.

Epidermal growth factor
• Human EGF is a 6045-Da protein with 53 amino acid residues
• Epidermal growth factors and their receptors are heavily involved in normal development,
differentiation, migration, wound healing and apoptosis
• Epidermal growth factor can be found in human platelets, macrophages, urine, saliva, milk,
and plasma.
• Most EGF family proteins are produced as inactive membrane -anchored proteins that
require proteolytic cleavage either to achieve activity in solution or bind to cell surface
proteoglycans from where they can act as a reservoir to be made available for receptor
binding.
Signaling in EGF
• A simple model to analyze signaling is by grouping it in to three layers
• The initial, extracellular layer is composed of the ligands and will dimerise to become active.
• If the information in the first layer is sufficient to induce receptor dimerization is achieved
by the s1 domain, Vander walls, hydrophobic interactions.
• consequently increase catalytic activity, will constitute the second
• The third, intracellular layer of second messenger proteins can bind to specific sites on the
receptors and initiate the signals required to induce the appropriate response.
• it is now evident that most or all of the ErbB family of receptors further aggregate into
oligomers of several hundreds or a few thousand receptors
• Erbb2 further has a higher catalytic activity than the rest furthermore when the other EGFR
combine with ErbB2 it wil increase their half life by decreasing the interaction with c-cb22,
AP2.

• The EGF Receptors monomer possesses an extracellular domain consisting of two ligand
binding subdomains (L1 and L2) and two cysteine-rich domains (S1 and S2), of which S1
permits EGFR dimerization with a second ErbB receptor. SH1 is the protein tyrosine kinase
domain and resides in the cytoplasmic domain above the six tyrosine residues available for
transphosphorylation.
The cytoplasmic region of the EGFR comprises three distinct domains:
• 1. the juxtamembrane domain, required for feedback by protein kinase C (PKC), down
regulation, epithelial basolateral polarity,
• 2. the noncatalytic carboxy-terminal tail, possessing the six tyrosine trans phosphorylation
sites mandatory for recruitment of adaptor/effector proteins (e.g. Grb2 and phospholipase
C (PLC) respectively) containing SH2 domains (src homology domain 2) or PTB
(phosphotyrosine binding) domains, plus the motifs necessary for internalization and
degradation of the receptor;
• 3. the central tyrosine kinase domain (src homology domain 1 (SH1)) that is responsible for
mediating transphosphorylation of the six carboxyterminal tyrosine residues.
• 4. it has serine threonine domains when phosphorylated it gets downgraded
• This domain is initially inactive, but once ligand binds it will become active.
• ERBB3 further increases the signaling activity by forming dimer with ERBB2 and trans
phosphorylating thus recruiting more second messengers or adapter complexes.
• Also stimulates enhanced and prolonged stimulation of the MAP kinase (ERK) and c-Jun
kinase (c-JNK) that would stimulate mobility, and cell cycle regulators like Mcl-2
Epidermal growth factor cont..

• the recruitment of the enzyme phospholipase C gamma (PLCγ). In its inactive state, PLCγ is normally
found in the cytosol.
• Upon its phosphorylation PLCγ, relocates to the membrane, where it makes contact with the
substrate Phosphatidyl triphosphate and ultimately generates the second messengers Inositol
(1,4,5)P3 and diacylglycerol.
• This activates calcium/calmodulin-dependent kinases and stimulation of protein kinase C.
• Protein kinase c that is activated by diacylglycerol phosphorylates NF-Kb and the inhibitor part is I-kb
when I-kb is phosphorylated the NF-Kb is released and activates various transcriptional factors that
would enhance proliferation and epithelial- mesenchyme transformation
• While through the influx of calcium calmodulin is activated and calmodulin woud phosphorylate
calcinurine, calcinurine intun dephosphorylate NFAT, then NFAT would go to the nucleus and activate
transcriptional factors.
• The MAPK and PI3K/Akt pathways promote cell proliferative and survival/antiapoptotic signals via the
activation of transcription factors and up regulation of cyclin D1.
• An increase in cyclin D1 that functions to sequester the cyclin kinase inhibitor p27 and release Cdk2.
• Subsequently, Cdk2 becomes positively regulated via its association with cyclin E and causes
deregulation of the G1/S checkpoint such that the cell cycle progression is promoted and leads to
malignant transformation.
• The downstream effectors of Akt also serve to sequester p27 such that the constitutive activation of
Akt that arises from c-erbB-2-overexpression is thought to confer resistance to tumor necrosis factor
induced apoptosis.
• Anti apoptosis is further upregulated by the release of P21
• Furthermore, Akt is known to stimulate endothelial nitric oxide synthase, matrix metalloproteinase,
and telomerase activity.
• It also up regulates synthesis if MDM2

EGF and cancer
The impact of the EGFR signaling system on human neoplasia is shown by the following:
1. EGFR is overexpressed or activated by autocrine or paracrine growth factor loops in at
least 50% of epithelial malignancies.
2. HER2 is amplified and dramatically overexpressed in approximately 20–30% of breast
cancers and also cervical cancers.
3. HER3 is variably expressed in breast and colon, prostate, and stomach malignancies.
4. ErbB4 is overexpressed in breast cancer and granulosa cell tumours of the ovary.
Also, ErbB2 overexpression by itself can cause cellular transformation even in the absence of
added ligand
• Also EGF is induced to be released from macrophages by the release of CSF 1
• Then the EGF will stimulate the epithelial to mesenchyme transformation of the carcinoma,
• This transformation aids in metastasis
• EGFR and ErbB2 have been showed to be overexpressed in a large proportion of breast and ovarian
tumours, primarily by gene amplification
• In cervical cancers, HPV E5 is known to cause overexpression of EGFR. Recently, ErbB2 was shown to
cooperate with HPV viral oncoproteins E6 and E7 to cause transformation.
• The trans membrane receptor Notch1 protein has been shown to overexpress ErbB2 and this along
with the ability of Notch1 to activate the PI3kinase PKB/Akt pathway and protect cells from apoptosis
and to protect cells from p53-induced cell death could play a major role in the progression of many
cancers like the cancer of the uterine cervix. where Notch is known to be overexpressed.
• It would be interesting to see whether Notch drives PI3kinase through overexpression of ErbB2 in
cervical cancers.

Platelet-derived growth factor
• Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits
(PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).
• PDGF is a potent mitogen for cells of mesenchymal origin, including fibroblasts, smooth muscle cells
and glial cells. In both mouse and human, the PDGF signalling network consists of five ligands, PDGF-
AA through -DD (including -AB), and two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as
secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers.
• Though PDGF is synthesized, stored (in the alpha granules of platelets), and released by platelets upon
activation, it is also produced by other cells including smooth muscle cells, activated macrophages,
and endothelial cells.
• There are five different isoforms of PDGF that activate cellular response through two different
receptors. Known ligands include A (PDGFA), B (PDGFB), C (PDGFC), and D (PDGFD), and an AB heterodimer
and receptors alpha (PDGFRA) and beta (PDGFRB). PDGF has few other members of the family,.
• Mechanisms: the receptor is classified as a receptor tyrosine kinase, a type of cell surface receptor.
Two types of PDGFRs have been identified: alpha-type and beta-type PDGFRs. The alpha type binds to
PDGF-AA, PDGF-BB and PDGF-AB, whereas the beta type PDGFR binds with high affinity to PDGF-BB
and PDGF-AB. PDGF binds to the PDGFR ligand binding pocket located within the second and third
immunoglobulin domains. Upon activation by PDGF, these receptors dimerise, and are "switched on"
by auto-phosphorylation of several sites on their cytosolic domains, which serve to mediate binding of
cofactors and subsequently activate signal transduction .Downstream effects of this include regulation
of gene expression and the cell cycle. The role of PI3K has been investigated by several laboratories.
Accumulating data suggests that, while this molecule is, in general, part of growth signaling complex, it
plays a more profound role in controlling cell migration. The different ligand isoforms have variable
affinities for the receptor isoforms, and the receptor isoforms may variably form hetero- or homo-
dimers. This leads to specificity of downstream signaling. It has been shown that the sis oncogene is
derived from the PDGF B-chain gene. PDGF-BB is the highest-affinity ligand for the PDGFR-beta;
PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis.

• PDGFs are mitogenic during early developmental stages, driving the proliferation of
undifferentiated mesenchyme and some progenitor populations. During later maturation
stages, PDGF signalling has been implicated in tissue remodelling and cellular
differentiation, and in inductive events involved in patterning and morphogenesis. In
addition to driving mesenchymal proliferation, PDGFs have been shown to direct the
migration, differentiation and function of a variety of specialised mesenchymal and
migratory cell types, both during development and in the adult animal
• PDGF plays a role in embryonic development, cell proliferation, cell migration, and
angiogenesis.
• PDGF is a required element in cellular division for fibroblasts, a type of connective tissue
cell that is especially prevalent in wound healing. In essence, the PDGFs allow a cell to
skip the G1 checkpoints in order to divide.It has been shown that in monocytes-
macrophages and fibroblasts, exogenously administered PDGF stimulates chemotaxis,
proliferation, and gene expression and significantly augmented the influx of inflammatory
cells and fibroblasts, accelerating extracellular matrix and collagen formation and thus
reducing the time for the healing process to occur.
• PDGF is also known to maintain proliferation of oligodendrocyte progenitor cells.It has
also been shown that fibroblast growth factor (FGF) activates a signaling pathway that
positively regulates the PDGF receptors in oligodendrocyte progenitor cells
Functions of Platelet-derived growth factor

Mechanisms of activation of proto-oncogenes
1. Promoter insertion
- In case of infection with retroviruses (RNA viruses), the cDNA of them is integrated into upstream long
terminal repeats (LTR) of the host DNA. These LTRs act as promoters of transcription.
2. Enhancer insertion
Also, in case of retroviruses infection, if the cDNA is integrated into downstream LTR, it acts as
enhancer of transcription of the gene.Both promoter and enhancer insertion can be classified as
insertional mutagenesis.
3. Point mutation
Such as missense point mutation at codon 12 in ras proto-oncogene Also, deletion that truncates certain
subtypes of EGFR leaves the receptor without extracellular ligand-binding domain and ligand-
independently active, e.g., in brain glial tumors.
4. Chromosomal translocation
- A piece of one chromosome is split off and then joined to another chromosome. One important
translocation is the “Philadelphia chromosome”, involving 9 and 22 and occurring in chronic
myelogenous leukemia (CML).
- Also, in Burkitt’s lymphoma which is the fast growing cancer of human B lymphocytes.
Chromosomes 8 and 14 are involved
5. Gene amplification
- It means the increase in copy number of a gene per genome, e.g., the amplification of the receptors for
certain growth factor, e.g., c-erb-B2 gene in brain glial and breast cancer.

Four important classes of regulatory genes responsible for cell division:
1. Promotors: Proto-oncogenes which can converted into oncogene by a mutation in
only 1 allele.
2. Inhibitors: Tumor suppressor genes such as Retinoblastoma (rb) gene and p53 gene.
Tumor suppressors are recessive – require mutation of both alleles
3. Genes regulating apoptosis.
4. DNA repair genes.
Molecular basis of carcinogenesis
Mechanism of chemical carcinogenesis
Generally, chemical carcinogens are electrophiles or can be metabolically converted to
electrophiles.
These electrophiles can react with nucleophilic centers (predominantly, N and O and to
some extent S) in cellular macromolecules such as DNA, RNA and protein.
The most dangerous result is the interaction with purines, pyrimidines or phosphodiesters
of DNA.
The common site of attack is guanine.
Steps of chemical carcinogenesis
1. Initiation 2. Promotion 3. Progression 4. Metastasis

Initiation
- Interaction of chemical carcinogens (Initiators) with DNA molecule to activate the
proto-oncogene or inactivate a tumor suppressor gene by formation of DNA adduct.
- Initiation step is rapid and irreversible.
Promotion
- Promoters are usually substances that stimulate cell activation and proliferation like
phorbol esters, hormones and some drugs may act as promoters.
- Some initiators can subsequently act as promotors (these are “complete
carcinogens”).
- Effect of promoter is reversible.
- The promoter cannot induce neoplasia, if:
i) alone,
ii) applied before initiator,
iii) applied in too small amount,
iv) too long time elapses between its applications.
Steps of carcinogenesis
Tumor progression
is the stepwise accumulation of mutations and increasing malignancy and is not simply
represented by an increase in tumor size i.e. many tumors become more aggressive
and acquire greater malignant potential.
During progression, tumor cells are subjected to immune and nonimmune selection
pressures. Cells that are highly antigenic are destroyed by host defenses.

Mechanisms of Metastasis
Invasion of Extracellular Matrix (ECM)
ECM
1-Basement membranes
2-Interstitial connective tissue (Composed of collagens, glycoproteins, and proteoglycans)
•Tumor cells live in a complex composed of ECM, growth factors fibroblasts, and immune
cells, with significant cross-talk among all the components
Invasion of the ECM is an active process that requires four steps
1- Detachment of tumor cells from each other (E-cadherins act as intercellular glues keep
the cells together )
• Tumor cells Detach from each other because of reduced adhesiveness
2- Attachment to novel ECM components
• Attach to the basement membrane via the laminin receptors and secrete proteolytic
enzymes, including type IV collagenase and plasminogen activator
3- Degradation of ECM
• Degradation of the basement membrane
4- Migration of tumor cells

Vascular Dissemination and Homing of Tumor Cells
• In the bloodstream, some tumor cells form emboli by aggregating and adhering to
circulating platelets and leukocytes, aggregated tumor cells are thus afforded some
protection from the antitumor host effector cells (most tumor cells circulate as single cells)
• Extravasation of free tumor cells or tumor emboli into the organ parenchyma by
mechanisms similar to those involved in invasion
Course of tumor emboli
•Tumors drained by systemic circulation lung left side of the heart other organs :
Bone, brain
•Tumors drained by the portal circulation liver Tributaries of hepatic vein lung and
other organs
•Abdominal, thoracic, pelvic tumors Vertebral veins Brain and spinal cord
Organ tropism
•Expression of adhesion molecules by tumor cells whose ligands are expressed
preferentially on the endothelium of target organs
• Site-specific homing involves chemokines and their receptors participate in directed
movement (chemotaxis)

Routs of Spread of malignant neoplasms
• Local (Direct) spread:
• Distant spread:
*Lymphatic spread (More common in carcinoma)
-Lymphatic embolism -Lymphatic permeation
*Blood spread (More common in sarcoma)
*Transcoelomic spread * Implantation
Local spread
•Malignant cells infiltrate the surrounding tissues in all directions along the line of least resistance
•Periosteum , bone, cartilage, elastic and fibrous tissue delay direct spread
•The direct infiltration occurs by the motility of malignant cells which lose adherence to each other
Lymphatic spread
• Lymphatic embolism
•The malignant cells invade the wall of lymph vessels, detach as small groups, carried by lymph as
emboli to the draining lymph nodes
•They are arrested in the subcapsular sinuses, destroy the nodal architecture and infiltrate the
surrounding tissue
•Spread to another lymph node of the same group is either by direct infiltration or efferent lymphatics
•The node becomes enlarged, firm and fixed
•Distant groups are affected later
• Lymphatic permeation
The tumor cells grow within the lumen of lymph vessels as solid cords to a variable distance from
primary tumors, it occurs in breast, prostate, and bronchial carcinomas

Blood spread
•The malignant cells invade the thin walled veins, detach and pass in the blood stream as tumor emboli
•As all lymph of the body drain into the venous circulation, carcinomas spreading by lymphatics will
finally reach thoracic duct giving tumor emboli in blood stream then to distant organs, it adheres to the
wall of capillaries, proliferate and produce secondary growths
Transcoelomic spread
•The tumor cells spread through serous sacs from affected organs covered by serous membranes,
infiltrated by tumor cells
•The cells detach and fall in the related sac then implanted on other organs, proliferate and metastasize
•The affected sac may show serous or hemorrhagic effusion due to occlusion of lymphatics, veins and
mechanical irritation by the tumor cells
Sites
•Peritoneal cavity is the commonest, especially in gastric and colonic cancer which give ovarian deposits
(Krukenberg tumor)
•Pleura and pericardium: Tumors of the bronchi and breast spread through pleural sac
•Malignant tumors of the brain if reach the surface, malignant cells shedded through cerebrospinal fluid
giving metastasis on ventricular lining at the base of the skull and on the dorsal surface of spinal cord
Implantation
•Through natural passages: As detected cells from cancer of renal pelvis which implanted on the mucosa
of urinary bladder
•Direct implantation: During surgical removal of malignant tumor, malignant cells may be implanted on
the wound

1-Self-sufficiency in growth signals
• Cancer cells do not need stimulation from external signals to multiply
• autocrine signaling ( self signaling) - by permanently activating the signalling pathways or by destroying 'off
switches' (negative feedback)
2- Insensitivity to anti-growth signals
• tumor suppressor genes
• Cancer cells do not have contact inhibition
• tumour suppressor proteins are altered so that they don't effectively prevent cell division
3-Evading Apoptosis
• altering the mechanisms that detect the damage or abnormalities
• defects in the downstream signalling itself, or the proteins involved in apoptosis
4-Limitless Replicative Potential
• Hayflick limit – 60 to 70 doublings before senescence
• 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the
Alternative Lengthening of Telomeres
• Telomerase keeps telomeres above the critical point
5-Sustained Angiogenesis
• continual supply of oxygen and other nutrients
• production of new vasculature by activating the 'angiogenic switch‘
6-Metastases
• Cancer cells break away from their site or organ of origin to invade surrounding tissue and spread
• dictates whether the tumor is benign or malignant
• Starts with normal invasion , then enters bloodstream
The 6 hallmarks of cancer

Biology of cancer

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