TEGENE ALEMU CANCER BIOLOGY SURGERY DEPARTMENT

Moderator – Dr Tilahun
=> (Assistant Prof. Of GI Oncology Surgery ,Consultant General & GI Oncology Surgeon)
Presenter – Dr Tegene (GSR1)

Outline
• Introduction
• Epidemiology
• Carcinogenesis and hallmarks of cancer
• Clinical picture
• Screening and prevention
• Management
3/11/2024 CANCER BIOLOGY 2

Introduction
• Egyptian Edwin Smith Papyrus, 3000–1500 BC
=>cure only by surgery thinking
• Cancer in the 16th -18th Centuries
 Scientific method and
 Autopsies introduced to the field use of Microscope
Harvey (1628) the first autopsy
John Hunter (1728-1793) surgical treatment
• Cancer in the Nineteenth Century
 Rudolf Virchow, cellular pathology
• In the early years of the 20th century
Tissue culture was developed.

Nomencture
• Derived from Greek word for crab, karkinoma
• Neoplasia
• Tumor, benign or malignant
• Cancer - Latin
• Stroma
• parenchyma
 Hippocrates (460–370 BC) coined the term carcinos
 Celsus (28-50 BC), later translated it into cancer

 Benign tumors of connective tissue… oma’
• Adipocytes – lipoma; Fibrocytes – fibroma
 Benign tumors of epithelial origin…
• Adenoma
• cystadenoma
• Papilloma
• Polyp
 Benign tumors of germ cells are called
teratomas.
Malignant tumors arising from connective tissues -sarcoma
• Fibrocytes – fibrosarcoma
• Osteoblasts – osteosarcoma
Malignant neoplasms of epithelial cells are called carcinomas
=>Spread via lymphatic except (BCC)
Malignant tumors arising form hematopoietic cells:
leukemia or lymphomas
Malignant tumors arising from germ cells
are teratocarcinomas (or malignant teratomas).

Benign Malignant
Grow slowly Grow rapidly
Well-defined capsule Not encapsulated
Not invasive Invasive
Well differentiated Poorly differentiated
Low mitotic index High mitotic index
Do not metastasize Can spread distantly
(metastasis)
Mitotic index = rate of growth
Describe growth of tumor
 Early exponential then
 slow b/c difficulty in ? nutrients &
oxygen

Epidemiology
• 2nd leading cause of death
• ~10 million death in 2020
• Beast ca is the commonest cancer diagnosed(2.26m)
• Lung ca is leading cause of death(1.8m)
WW
• Lung, Prostate, CRC
• Breast, Lung, CRC
ETHIOPIA
• CRC, Prostate,Leukemia
• Breast, cervical,CRC
SEX
• MALE
• FEMALE

Cell cycle
**Cancer Cell ->G0 (Quiescent ) By
Pass (not enter G0) ->PROLIFERATION
Of Cancer cell
WHY ?
 Function - Cell growth & divide
 4-Phases => G1-S-G2-M
 G0 (Resting cell)- cell under go terminal differentiation.
=>cell perform function with out preparing for cell division &
=>some restart division after right signal

Apoptosis (Program cell death)
Initiate by two paths ;-
 Intrinsic –Cell kill it self by sense stress signal by BH3.
 Extrinsic – Cell kill it self senses by other cell and bind EC
Death ligand (Fasl,TNF..)
Proteins and modulators that promote apoptotic cell death are shown in blue, inhibitors are shown in
red
Caspase -Effector Apoptosis Protein
 Initiator Apoptosis Caspase -8,9 & 10) upstream
 Executioner caspase (3,6 & 7) cleave down
stream while cancer cell downstream stimulate
Apoptosome (enzyme activate caspase)
Growth tumor rate depend not only on
increase proliferation tumor cell But also
decrease Apoptosis.
WHY ?
 When Cell Get old under go phagocytosis
 Necrosis -Repair if not repair under go apoptosis/
stimulated by many factors,
including DNA damage, reactive
oxygen species, or the withdrawal
of survival factors
form a death-
inducing signaling
complex (DISC)

Carcinogenesis
• Multistep process – Hallmark of Ca.
• Initiation, promotion and progression
• Tumor cells undergo genetic changes
• Stroma undergo phenotypic changes
• Darwinian selection
• Leads to growth advantage and tumor progression
Genetic lesion
• Point mutation
• Gene rearrangement
• Deletion
• Amplification
• Aneuploidy
Pro oncogene over expressed
DNA Damage=>Mutation=>Malignant
Cancer genes + Enabling factors
20% of all tumors have
activating mutations in one of
the ras genes by cancer type
(e.g., 90% of pancreatic
cancers, but 5% of breast
cancers

CRC carcinogenesis
• Colorectal tumors arise from the mutational activation of oncogenes coupled
with mutational inactivation of tumor-suppressor genes, the latter being the
predominant change.
• Mutations in at least four or five genes are required for formation of a
malignant tumor, while fewer changes suffice for a benign tumor.
Other
?APC tumor-suppressor gene) is abnormal in what percentage of sporadic (nonsyndromic) colon
cancer? 80%
 Earliest known genetic alterations in colorectal cancer progression

Cancer gene
• Oncogenes
• Tumor suppressor genes
• Genes that regulate apoptosis
• Genes that regulate interaction
between cancer cells and host cell
ONCOGENES - May be
 Growth factors (e.g., platelet-derived growth factor)
 Growth factor receptors (e.g., HER2)
 Intracellular signal transduction molecules (e.g., ras),
 Nuclear transcription factors (e.g., c-myc), or
 Other molecules involved in the regulation of cell growth and proliferation
Growth factors are ubiquitous proteins that are
produced and secreted by cells (Autocrine &
paracrine) .
=>uncontrol proliferation
DNA Damage=>Mutation=>Malignant
Cancer genes + Enabling factors

HER 2 Signal pathway
• Member of Epidermal GFR
• Mitogenic & antiapoptotic oncogen
• Heterodimer & Indirect soluble ligand
• Key role on cancer biology b/c tumorgenicity
,Angiogenesis & metastasis
• HER 2 Target drug BY FDA (Transtuzumab, pertuzumab
HER 2 Family

Epigenetics and cancer
 Reversible changes in DNA and histone
 Hypo methylation and posttranslational
modifications
Enabling factors
A. Genomic Instability – inherited predisposing for
ca
EX - Retinoblastoma –RB gene
B. Tumor-Promoting Inflammation –
• Release of factors that promote proliferation
• Hall mark of cancer cell
Chronic inflammatory conditions-
Ex- IBD - CRC
Precursor lesions
• Squamous metaplasia and dysplasia of bronchial mucosa
• Endometrial hyperplasia and dysplasia
• Leukoplakia of the oral cavity, vulva, and penis
• Villous adenoma of the colon

Enabling factor
 Genomic
instability

What are ‘ hallmarks of cancer ‘ ?
• Biologic capabilities acquired by cancer cells during the multistep
process of development of human tumors
• Essential Alterations In Cell Physiology That Collectively Lead To
Malignant Growth Of A Normal Cells.
• Described by Douglas Hanahan & Robert Weinberg in 2000

Originally 6 + 2 hallmarks of cancer proposed
Although there are >100 types of cancer,
• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory (antigrowth) signals.
• Limitless replicative potential ( )
• Evading apoptosis.
• Sustained angiogenesis.(Neogenesis)
• Tissue invasion and metastasis.
S
I
L
E
N
T,
E
D
,
G
T
somatic mutation -
 + down stream path (RAS-MAF-MAPK Path way
 XNF
• The two prototype tumor suppressor genes encode the
=>Retinoblastoma (RB)-associated and P53 proteins.
=>TGF-B & Contact Inhibition, NF2, and wnt pathway
Cancer cells acquires anti apoptotic regulators, Autophagy ,Necrosis
 Loss P53 Function
 Inc. Antiapoptotic regulator (BCL,MCL..)
 Downregulate proapoptotic –BCL-2
Activation of an enzyme ( telomerase) can maintain
telomeres =>replicate limitlessly B/C Loss P53 function.
Angiogenic Switch Of Tumors – VEGF,FGF,TGF
MUTATION TGS & Pro oncogene Invading =>motility increase -
plasmin w/c activate MMP degraded ECM promote ca
progression -> MAGPA

Hallmarks of cancer
1;somatic mutation -
 + downstream path (RAS-MAF-
MAPK Path way
 No negative feedback
2;The two prototype tumor suppressor genes encode the
=>Retinoblastoma (RB)-associated and P53 proteins.
=>TGF-B & Contact Inhibition, NF2, and wnt pathway
3;Activation of an enzyme ( telomerase) can
maintain telomeres =>replicate limitlessly B/C
Loss P53 function.
4;Cancer cells acquires anti apoptotic
regulators, Autophagy ,Necrosis
=>Loss P53 Function
=>Inc. Antiapoptotic regulator (BCL,MCL..)
=>Downregulate proapoptotic –BCL-2
5;Angiogenic Switch Of Tumors – VEGF,FGF,TGF
8;use Aerobic glycolysis to
produce lactate (acidification &
nutrient)
7;Tumor induce immune suppression &
self antigen, self barrier
NB- With development in genetics and epigenetics Hanahan and Weinberg again redefined
“Hallmarks of cancer” in 2011
Release of factors that promote proliferation
Chronic inflammatory conditions-
Ex- IBD - CRC
6;MUTATION TGS & Pro oncogene Invading
=>motility increase -plasmin w/c activate MMP
degraded ECM promote ca progression -> MAGPA
Inherited predisposing for ca

1.Sustained Proliferative Signaling
Cancer cells : ‘master of their own destinies’
• Normal cells require growth signals to enter from a quiescent state into an
active proliferative state.
• Signals are transmitted into the cell,trasmembrane receptor bind signal
molecule
• Tumor cells generate their own growth signals and reducing external
stimulation from their normal tissue microenvironment.
Cancer cells acquire growth self-sufficiency via alteration of:
• Growth factors
• Growth factor receptors
• Downstream signal transmitting proteins

CONT…
 RAS is the most commonly mutated oncogene in human tumors.
 ~30% of all human tumors contain mutated RAS genes
 RAS is a member of a family of G proteins that bind GTP and GDP.
 Normally found In quiescent state binding GDP
 When activated it binds GTP…has gtpase activity
Somatic Mutations activate additional downstream pathways that promote
sustained growth
• RAS-RAF-MAPK PATHWAY
• 90% Pancreatic adenocarcinomas carry mutant K-RAS alleles
• 40% melanomas contain activating mutations affecting B-RAF
Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative
Signaling
• The prototype of this type of regulation involves the
Excessive Proliferative Signaling Can Trigger Cell Senescence
• Signaling by oncoproteins, such as RAS, MYC, and RAF in a normal cell
provoke protective response such as induction of cell death.

2. Evading Growth Suppressors
A.
3/11/2024 CANCER BIOLOGY
22
• Growth suppressors are acting as the break mechanism to
overrule the initiation or “turning off” of cell division.
• The two prototype tumor suppressor genes encode the
 Retinoblastoma (RB)-associated and
 P53 proteins.
• The RB protein integrates signals from diverse EC & IC
sources and, in response its growth and division cycle
G1-Arrest

Cont…

Cont …
C. Transforming Growth Factor-β
Growth inhibitor In normal cell
• Activation of growth-inhibiting genes such as CDKIs and
• suppression of growth-promoting genes such as MYC and cyclins.
D. Contact Inhibition, NF2, and wnt pathway
• E-cadherin
*APC
Role of TGF-B
• In normal cells, its exposure blocks their
progression through the G1 phase of cell cycle;
• In cancer its signaling is redirected away from
suppression to activation of a cellular program
termed
“epithelial to mesenchymal transition
• Merlin, the cytoplasmic NF2 gene product, activate STRENGTH CELL
TO CELL ADHESION and thus inhibits the mitogenic signals.
• Thus, the mutation of NF-2 gene results in loss of this property and
thus grow in uncontrolled manner.

3. Resisting Cell Death
• Cancer cells acquires anti apoptotic regulators:-
• Autophagy Mediates Both Tumor Cell Survival and Death
• Necrosis has proinflammatory & tumor promoting potential
Cancer cells acquires anti apoptotic regulators:-
•Most common is the loss of P53 tumor suppressor function,
•Alternatively, tumors may escape apoptosis by -
-Increasing the expression of antiapoptotic regulators (Bcl-2, Bcl XL, Mcl-1).
•By downregulating proapoptotic Bcl-2–related factors (Bax,Bim,Apaf-1 ).

cont …
Autophagy Mediates Both Tumor Cell Survival and Death
• Nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels
of autophagy that apparently protect cancer cells via resistance to apoptosis.
• Moreover, severely stressed cancer cells have been shown to shrink via autophagy to a
state of reversible dormancy.
• This particular survival response may enable the cancer cells to survive during
anticancer therapy or during shortage of nutrition.
Necrosis has proinflammatory & tumor promoting potential
• Necrotic cells can release bioactive regulatory factors which can directly stimulate
viable neighboring cells to proliferate

4. Enabling Replicative Immortality
• In normal cell division, a small portion of the end
of each chromosome called telomere, is lost
every time DNA is copied.
• Loss of telomere -> No longer divide and
replicate and undergo p53 dependent cell cycle
arrest or apoptosis
• But in cancer cells activation of an enzyme called
telomerase can maintain telomeres and allow
cells to replicate limitlessly

5. Inducing Angiogenesis
The formation of new blood vessels out of
pre-existing capillaries.
ANGIOGENIC SWITCH OF TUMORS
INVOLVES :
Sprouting
Splitting
Remodeling of the existing vessels
WHY IT IS IMPORTANT?
Supply of oxygen and nutrients
Removal of waste products

6.INVASION AND METASTASIS
Steps in activating invasion and metastasis
Carcinoma development and acquire invasive potential-
• Tumor suppressor genes mutation
• Proto oncogene mutations
Expansion of growth and invasion of basement membrane
• Enhanced protease activity(e.g. MMPs)
• Enhanced cell motility / interaction with surrounding tissue.
• Decreased cell to cell adhesion and contact( e.g.E-cadherin loss)
Intravasation and transport through BM
• Intravasation through BM into blood vessel.
• Interaction with vascular cells
• Survival in circulation / immune eversion
motility increase -plasmin w/c activate MMP
degraded ECM promote ca progression -> MAGPA

Epithelial to mesenchymal transition program
(EMT)

7.Reprogramming Energy Metabolism
• Cancer metabolism is different than normal tissue metabolism.
• First time noted in 1920 by biochemist Otto Warburg that when
cancer cells are provided with glucose , they generate large amount
of lactate regardless of whether oxygen is present or not.
• This metabolic difference is referred as THE WARBURG EFFECT……
Aerobic glycolysis energy less than aerobic respiration pr
 Not for energy source but Lactate for acidification of tumor cell
,promote invasion & metastasis
 lactate also use as nutrient
• Warburg effect and also known as aerobic glycolysis
• “glucose-hunger” of tumors is PET scanning
• Autophagy :is a state of severe nutrient deficiency

metabolic ...
Mutation in metabolic enzymes Causing cancer
• FH [fumarate hydratase]– metabolizes fumarate in TCA…mutation leads to RCC ,leiomyomas.
• IDH [ isocitrate dehydrogenase]– in glioma, glioblastoma, AML, myelodysplastic syndrome, ALL,
prostate, colorectal cancer.
Targeting metabolism to treat cancer
• FOLATE -ANTI FOLATE use as CT (Chemotheraphy)
• Metformin - Mortality is decreased with metformin use—may be
toxic to the cancer cell—may decrease the effect of IGF-1 on cell growth

8.evasion of immune
Mechanisms by which tumor cells escape immune
Recognization and destruction:
• Low immunogenicity of tumor cells –
• Failure to produce tumor antigen
• Mutation in MHC gene needed for antigen processing.
• Inability to recognize tumor cells by immune system
Immunosuppressed patients have an increased risk
Immunocompetent patients, tumors may avoid the immune syste

Cont....
Tumor induced immune supression-
• Factors secreted by tumor cells eg. TGF-b inhibit T
cells directly.
Tumor induced privileged site-
• create a physical barrier to the Immune system.
Tumor treated as self antigen-
Taken as self antigens and escape from immune
Destruction.

Carcinogenic agents
• Three classes of carcinogenic
agents
• 1. Chemicals
• 2. Radiant energy, and
• 3. Microbial products

carcinogen

Clinical aspect of neoplasia
- Effects of Tumor on Host
• Cancer Cachexia
• Paraneoplastic Syndromes
• Grading and staging of cancer
Routes Of Spread
1.Direct extension
2.Lymphatic Spread –
=> Common in epithelial neoplasms of all types (except
for basal cell ca)
3.Vascular spread -
Either thru the thoracic duct or by the invasion of blood
vessels
Capillaries are almost invaded, veins invaded frequently
but arteries rarely.
More common in sarcoma
4- Spread through serous cavities
Peritoneal seedings (gastrointestinal CA)

Clinical manifestation
The onset of neoplastic state is difficult to date (asymptomatic).
Seven Danger Signals of Cancer (Direct manifestation):
1. Change in bowel or bladder habits
2. A sore that does not heal
3. Unusual bleeding or discharge
4. Thickening or lump in breast or elsewhere
5. Indigestion or difficult in swallowing
6. Obvious change in wart or mole
7. Nagging cough or hoarseness
Indirect or Systemic Manifestation:
1. Secondary to metastasis
Cachexia
2. Secondary to none metastatic:
a. Ectopic production of known hormones
b. Secretion of unidentified, hormone like substances
c. Toxic substances secreted from the tumor
d. Autoimmune – host is sensitized to antigen from tumor.
Signs of Expansile growth:
1. Obstruction
2. Destruction
Signs of Infiltrative Growth:
Tumor infiltrates the nerves
1. Pain
2. Numbness
3. paralysis
Signs of Tumor necrosis (Bleeding & Infection):
Tumor may become necrotic, ulcerate and bleed
Fatigue and weakness in right colon cancer due to anemia
Inflammation caused by cecal CA can mimic the clinical
symptoms of acute AP or cholecystitis.
Unknown primary tumors presenting as metastases

A. Clinical History: -Warning signs for Cancer:
B. Physical Examination:
Palpable masses (movable, nonmovable)
LN enlargement
C. Laboratory Examination:
 Blood examination – tumor marker
 Biopsy -
 Radiological procedure:
 X-ray, esophagoram, Barium enema,
 Mammography, Thyroid scan, CT scan,MRI
D. Endoscopy:
• Bronchoscopy, Esophagoscopy
• Gastroscopy, Proctosigmoidoscopy,
• Colonoscopy, Cystoscopy

Biopsy
• To document presence of malignancy Types:
• 1. Needle biopsy (cytological)
• 2. Incisional biopsy
• 3. Excisional biopsy
• Rapid frozen biopsy / exfoliativecytology (Pap
smear)

Grading and staging of cancer
• Grading: degree of differentiation
• Staging: size, LN and distal metastasis
. => TNM system
Microscopic examination also provides information regarding the likely behavior of a
tumor and its responsiveness to treatment.
In this grading system,-
• a low number grade (grade I or II)
refers to cancers with fewer cell
abnormalities than those with
• higher numbers (grade III, IV).

Staging of cancer
A. Clinical staging of Cancer: TNM:
Stage I = cancer confined to it’s primary site
Stage II = more locally advanced disease
Stage III = metastasis to regional LN
Stage IV = metastasis to distant sites
Use all information available prior to 1st definitive Rx.
B. Post-surgical Resection Staging:
Pathological Staging:
The extent of disease using all data available at the time of
surgery and on examination of a completely resected specimen.
C. Re-treatment Staging:
Restaging is necessary for additional or secondary
definitive treatment after a (disease-free) interval
following 1st treatment.
D. Autopsy Staging:
Used only when the cancer is 1st diagnosed at
autopsy

Screening of cancer
• That is why screening for some cancers is important,
particularly as you get older.
• screening methods are designed to check for cancer in
people with no symptoms.
CERVICAL Cancer Is One Of The Commonest Female Cancer Next To Breast Cancer In Ethiopia
Screen From Age 21-65

Breast ca Risk women -age
>40
 Start at 45
 45-55 ANNUALLY
 >55 –BIENNIA
 LG/EL 10YR
CRC START @50
 Q1-FOBT
 Q5-FSIG,DCBE,CT Colonography
 Q10-COLONOSCOPY
 Lung Ca At 50-74
 Healthy 30py &
 CURRENT Smoke
Or Quiet 15 Ago

Cancer treatment
GOALS of Therapy:
Vary w/ extent of the cancer:
1. Localized w/o evidence of spread: Eradicate the cancer and CURETHE PATIENT
2. Spread beyond the local site:
Control patient’s symptoms and to maintain maximum activity for the longest
possible period of time.
CRITERIA of Incurability:
1. Distant metastasis (most common)
2. Evidence of extensive local infiltration of adjacent organs or structures
Pt’s general condition and co-existing disease must be considered in planning therapy.
The PSYCHOLOGICAL makeup of the patient and the patient’s life situation
must be considered.

Cancer treatment …
Surgical Curative Resection:
Wide local resection:
Low grade malignancy
Basal cell CA of the skin
Radical Local Resection:
High grade malignancy
En Bloc LN dissection for breast,esophagus, gastric,
colorectal CA
C.
Surgical Palliative Resection:
1. To relieve symptoms
2. To prolong a useful comfortable life
3. Gastrojejunostomy, colostomy
RADIOTHERAPY:
Destroy tumor with preservation of anatomic
structures
Direct toxic effect to cells due to ionization of
water

Cancer treatment …
Chemotherapy
Antimetabolites:
Inhibit enzymes of nucleic acid synthesis
Methotrexate & 5-FU
Alkylating agents:
Substitute alkyl grp for the hydrogen atom
Alkylation of DNA molecule interferes with replication in
transcription
Antibiotics:
From soil fungi
Forms stable complexes with DNA and inhibit synthesis of
DNA and RNA
Actinomycin D, Doxorubicin, Bleomycin
Vinca Alkaloids:
Bind to microtubular proteins necessary for cell division
causing cell death during mitosis
Vincristine & Vinblastine
IMMUNOTHERAPY:
Inhibit proliferation of cancer cells w/o
affecting function of normal cells
Stimulates the host to generate specific
immune response to its tumor-vaccine from
tumor cells
TUMOR SPECIFIC ANTISERUM:
Murine monoclonal antibodies
Immunotoxins
None-specific immunotherapy=BCG vaccine
DETERMINANTS:
1. Site of origin of primary tumor
2. Stage of the disease
3. Histologic features of the cancer
4. Host immune factors
5. Age of the patients

Cancer treatment …summary
• SURGERY Is The Gold Standard – CRC, Breast Ca, Ovary ,Lung, Thyroid, Skin, Uterus,
Prostate
• CHEMOTHERAPY – Lymphoma, leukemia, testicular, choriocarcinoma, ovary ,Breast
• RADIOTHERAPY – Breast, Uterus, Cervical, Lymphoma, Lung
• HORMONAL THERAPY – Breast, Prostate, Endometrium, Adrenal
• IMMUNOTHERAPY – Melanoma, RCC, leukemia
• TARGET THERAPY –Colon, breast, lung, RCC, leukemia, lymphoma

Role of surgery in malignancy management
Treat the primary tumor
Treat complication
To remove isolated metastasis
masses
To remove a source of hormone –PT
Adenectomy ,Orchidectomy
Debulking
Diagnostic and Staging
 Prevention
 Palliative
 Provide access for chemotherapy
delivery (implanted
infusion/pump)
 Reconstructive anatomic defect
for improve function, cosmetic
and quality of life

Reference
Robbins basic pathology, 10th edn
WHO global Cancer observatory, 2020
Google +

TEGENE ALEMU CANCER BIOLOGY SURGERY DEPARTMENT

Recommended

Recommended

More Related Content

Similar to TEGENE ALEMU CANCER BIOLOGY SURGERY DEPARTMENT

Similar to TEGENE ALEMU CANCER BIOLOGY SURGERY DEPARTMENT (20)

Recently uploaded

Recently uploaded (20)

TEGENE ALEMU CANCER BIOLOGY SURGERY DEPARTMENT