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BHS 116.3 – Physiology III
Notetaker: Vivien Yip
Date: 4/24/2013, 1st hour
Page1
Lecture 31 Chemical carcinogens, viral carcinogens, host defense against tumors, grading and
staging
Chemical Carcinogenesis
- 2 step process
o 1st step: Initiation
 Results from exposure to carcinogenic agent (chemical, radiation)
 Causes permanent irreversible DNA damage
 Not sufficient for tumor formation
o 2nd step: Promotion
 Can induce tumors from previously initiated cells
 Not tumorigenic by itself
 Does not affect DNA directly (promoter itself)
 reversible
 usually a growth factor or some other cellular stimulus that activates DNA
transcription with the damaged DNA
Initiation and Promotion
- Initiation
o Causes permanent DNA damage
- Memory
o Damage is permanent and irreversible
- Promoters
o do not effect DNA directly and are reversible
o require previous initiation to cause tumors
Group 1- only initiation occurs, irreversible DNA
damage, nothing follows it, no promotor, no tumor
formed
Group 2- initiation then sequential application of
promoter following initiation, a lot of promoter in
a short period of time  tumor
Group 3 – will have nothing after first set of
initiation, then promoters are added and trigger
tumor formation  tumor
(Key: a lot of promoters in short period of time in
close proximity will cause tumor if the DNA has
been initiated)
Group 4- initiation has to occur prior to promoter
 no tumor
Group 5- No initiation, only promoter  no tumor
Group 6- initiation occurs (irreversible DNA damage), promoter is applied in minimal amounts, spaced
out over long period of time, not going to trigger tumor (require cluster of promoter application to get
tumor)  no tumor
Carcinogenic Chemicals
- diverse in structure
- natural OR synthetic
- direct OR indirect (procarcinogens)
o procarcinogens require metabolic step to become carcinogenic*
o i.e benzoapyrene is found in cigarette smoke
BHS 116.3 – Physiology III
Notetaker: Vivien Yip
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Date: 4/24/2013, 1st hour
Page2
o more indirect carcinogens than direct carinogens
highly reactive electrophiles that react with electron rich sites in cells (DNA, RNA and proteins)
Chemical carcinogenesis
- most chemical carcinogens are procarcinogens and
require metabolic activation to form the ultimate
carcinogen
- in most cases, carcinogens are detoxified in liver
and excreted via urine/bile, usually not a problem
- can be some direct carcinogens that can lead to
DNA damage
- also potentially some that are converted
(procarcinogen  more active carcinogen)
o these intermediates can sometimes be
detoxified via liver and excreted
- some carcinogens can evade the liver and cause
DNA damage
- DNA repair genes can repair damaged DNA if
carcinogen is able to act on it
o can trigger apoptosis if DNA is mutated
- Some carcinogens damage DNA beyond help of p53
and RAS  will cause tumor since repair process is
stopped
- primary targets for mutation are RAS and p53 (most commonly affected*)
- multistep process with checks and balance in place, carcinogens that evade this will cause a tumor
Radiation carcinogenesis
- UV rays from sunlight and ionizing radiations
- X rays, gamma rays, protons, neutrons
- Can transform all cell types
- irreversible damage
UV Radiation
- Can inhibit cell division
- Can inactivate enzymes
- Can induce gene mutations  pyrimidine dimers
o major reason for DNA damage
- Can kill cells, i.e. extensive sunburns
Ionizing Radiation
- Both electromagnetic (x rays and gamma rays) and particulate (alpha, beta particles, protons &
neutrons) are carcinogenic
- cause irreversible DNA damage
- Most frequent radiation induced cancers are leukemias (except chronic lymphocytic leukemia)
with thyroid cancers in the young being the 2nd most common
- Skin, bone, and GI tract are relatively resistant to ionizing radiation induced cancers
Viral carcinogenesis
- DNA VIRUSES
o Form stable associations with host cells genome
o Papillomaviruses
BHS 116.3 – Physiology III
Notetaker: Vivien Yip
Date: 4/24/2013, 1st hour
Page3
 Involved in pathogenesis of warts to carcinoma
 new vaccine for cervical cancer (Gardisil)
o Epstein barr virus
 Involved in the pathogenesis of Burkitt lymphoma and Hodgkin disease
o Hepatitis B virus
 involved in pathogenesis of liver cancer
- RNA VIRUSES
o Human T cell leukemia virus type I
 T cell leukemia/lymphoma
Epstein barr virus
- EBV serves as one factor in the development of Burkitt lymphoma
o Effects primarily B cells
- viruses integrate their genome into host cell
o cells will express viral genes (viral oncogenes) in
host cell
o cell becomes tumorogenic
o get transformed B cells, some get recognized by
cytotoxic T cells  destroyed, will not
proliferate to tumor cells
o some that evade the immune system, express
EPV antigens on their surface
o one of the things triggered by the virus is
chromosomal translocation
 b/w chromos 8 & 14
o Mutation of oncogene MYC
 gets expressed and trigger tumor
formation, proliferation of a number of B
cell tumors
 excessive proliferation of mutant B cell
 blood cell cancer, do not get actual tumors
Human T cell leukemia virus type I (HTL)
- RNA virus
- Transmitted by sexual contact or blood transfusion
- First infected T cells (CD4+) proliferate due to
autocrine and paracrine cytokine stimulation
o Due to viral protein, TAX, which
increases IL2 AND IL2r (receptor)
expression, while inhibiting tumor
suppressor genes
o CD4+ T cell will be producing high levels
of IL2 (proliferation phase of CD4+ T
cells when they activate) and IL2r 
cytokine released, binds to own receptor
and triggers increased proliferation
o TAX = oncogene in HTL virus
- Ultimately one T cell clone mutates during the
great amount of replication
o results in malignancy
BHS 116.3 – Physiology III
Notetaker: Vivien Yip
Date: 4/24/2013, 1st hour
Page4
Hallmarks of Cancer
- Most cancers will acquire these properties during their development over time as the tumor
proliferates inside the body (to evade our immune system or being destroyed)
o Evade apoptosis
o Self-sufficient growth signals (can’t rely on growth factors secreted by the rest of the
body)
o Insensitive to antigrowth signals (our body uses this to destroy the potential tumor)
o Metastasis (spread to other sites)
o Limitless replication (highly active telomerase, CA cells can go through limitless
replication)
o Sustained angiogenesis (has to have its own blood supply, tumors can only survive
through their own blood supply to sustain their highly metabolic activity)
Host Defense Against Tumors
- Our bodies are exposed to carcinogens all the time, we are very good at getting rid of these
tumor cells, alerts are in place to activate immune system
- 1.Overexpressed Antigen
o Present in both normal and tumor cells
o Low levels in normal cells result in non detection by T cells
- 1.Aberrantly expressed
o MAGE family of genes are antigens usually silent in normal cells and expressed in tumor
cells
o Also expressed by immunologically privileged tissue in testes
o liver cells have genes for all cells, if something disrupts that cell so that it is expressing
normally immune privileged antigens (testicular or ocular antigens, where it shouldn’t
belong) on its surface, that will signal the immune something is wrong
- 2.Mutated self protein
o Various normal self proteins can be mutated by carcinogens (chemicals, radiation)
o Protein is mutated
- 3.Antigens resulting from mutant oncogenes
o Mutants present only in tumor cells
o Gene is mutated and produces a mutant protein
o RAS becomes mutated and continuously hydrolyzes GDP to constantly become active
o No evidence that this occurs naturally
o Requires an initiator
- 4.Viral Antigens
o Viral genes (oncogenes) expressed in tumor cells by oncogenic virus
Anti tumor mechanisms
- Both cell mediated and humoral immunity can have antitumor activity
o Cytotoxic T cells (CD8+)
 Attack cells expressing peptide-MHC
class 1
 previously activated by specific Ag
 will go after all those cells that expresses
“non self Antigen”
 especially viruses, viral peptides are
expressed via MHC 1
 will end up triggering CD8 + cells
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BHS 116.3 – Physiology III
Notetaker: Vivien Yip
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Date: 4/24/2013, 1st hour
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NK cells
o May provide first line of defense as no prior sensitization is necessary
o Attack tumor cells with lowered levels of MHC class I (or lack of MHC I)
o Can also participate in ADCC , Antibody Dependent Cell Cytotoxicity, Antibody
produced against specific tumor antigen and binds to tumor cell, NK cell can recognize
the antibody (Fc receptors), binding triggers destruction
Macrophages
o Activated macrophages can be cytotoxic to tumor cells
 Phagocytosis, especially through ADCC
 Cytokine secretion, draws in WBC to site
Antibody
o Targeting for complement activation
o ADCC
o can form MAC on tumor cell and lead to lysis
CD4+ also plays a role in activating the B cell to cause class switch, activates macrophages
Grading & Staging of tumors
- Grading of a cancer is based on degree of differentiation of the tumor cells and the number of
mitoses within the tumor
o Correlates with the neoplasm’s aggressiveness
- Tumors are classified as grades I-IV with increasing anaplasia
o I- well differentiated (benign tumor, look exactly like tissue they originated from)
o IV- completely undifferentiated (anaplastic, looks nothing like host organ malignant
metastatic tumor)
- Staging is based on the size of the primary lesion, extent of spread to regional lymph nodes and
the presence or absence of blood borne metastases
- Staging has proved to be of greater clinical value than grading, more accurate
- 2 systems used:
o TNM classification
 T for tumor (T1, small-T4, large  for increasing size)
 N for lymph node involvement (N0, no involvement-N3, significant amount of
lymph nodes for increasing range and # of nodes involved)
 M for metastases (M0, no metastases-M2, significant amount of metastases)
 Varies for each form of cancer
o AJC system (American joint committee on cancer staging)
 Cancers divided into stages 0, benign – IV, metastatic tumor which
incorporates the size of the lesion as well as nodal involvement and metastases
Laboratory diagnostics
- Histology and exfoliative cytology (smears) are the most commonly used techniques in the
diagnosis of cancer
- In order to get the tissue, we have various ways:
o Excision or biopsy
 Appropriate preservation of the sample is critical (preservation/freezing)
o Fine needle aspiration
 Sample is aspirated by a needle and stained before examination
o Cytologic smears
 Cancer cells have a decreased adhesiveness (scraped off a lot easier) and are
morphologically different
- PAP Smear (papanicolaou)
o Normal cells are large and flat and very adherent
BHS 116.3 – Physiology III
Notetaker: Vivien Yip
Date: 4/24/2013, 1st hour
Page6
Cervical tumor cells are not adherent and have a lot more cells present in the smear 
very easy to distinguish
o Cancer cells have large hyperchromatic nuclei, polymorphic nuclei and mitotic cells
- Newer techniques are continually being added to improve diagnosis of various cancers
o Immunohistochemistry
 Allows for categorization of undifferentiated malignant tumors, determination of
site of origin of metastatic tumors, detection of molecules with therapeutic
significance
 stain sample with different antigens, i.e. lung biopsy (liver antigens present =
originated in liver and metastasized in the lung)
 i.e. anticytokeratin antibody to identify epithelial origin
o Tumor markers
 Biochemical markers of various cancer types
o Molecular diagnosis
 Useful in diagnosis as well as predictive and therapeutic aspects of cancer
 screening tool for certain genes that lead to cancers
Cancer Tx
- Chemotherapy
o Anti-mitotic drugs/drugs that interfere with DNA replication
- Radiation tx
o Causes a lot of collateral damage
- Surgical removal
- Biological therapy
o Enhancement of immune system (interferons & interleukins)
- Gene therapy
- Targeted cancer therapy
o Drugs that interfere w/ carcinogenesis, anti-angiogenesis drugs
o prevent collateral damage
- Radiofrequency ablation?
o Novel technique, not FDA approved
o Small amounts of metals that burns the tumor with radiofrequencies
o
Clicker Q
Which of the following processes is reversible?
- initiation of carcinogenesis
- promotion of carcinogenesis