Exam 2: Oncogenesis Flashcards
Virus Association to Cancer (5)
o HPV, cervical
o Epstein-Barr Virus (EBV), mono, lymphoma, nasopharyngeal carcinoma
o Kaposi sarcoma herpesvirus
o Hepatitis B and C, hepatocellular carcinoma (liver)
o HIV, leukemias
what are all forms of cancer related to?
all forms of cancer are related to inherited or acquired genetic mutations
the pattern of cancer occurrences
may be inherited, familial, or sporadic
what are inherited forms of cancers due to?
due to germ line mutations and may account for about 5 to 10 percent of all cancers
Example: women with heredity breast and ovarian cancer have a germ-line mutation in either BRCA 1 or BRCA 2. Most common in people of Ashkenazi Jewish decent, HNPCC or heredity nonpolyposis colorectal cancer, has a hereditary link and is also known as Lynch syndrome
95% of the time, cancer are sporadical in nature and they are somatic, what does somatic mean?
they are acquired, usually something in the environment. toxic to DNA
hallmarks of hereditary cancers (4)
o Early age onset: less than 40-50 years for adult onset cancers
o Multiple primary cancers in a single individual
o Bilateral cancers in paired organs
o Uncommon presentations of cancer
environmental factors for cancer
o Diet, lifestyle sun exposure up to 90% of cancers are linked to environmental factors
o Breast, colon, prostate cancers may be modulated by hormonal systems including estrogens, androgens, insulin
o Increased fasting insulin levels are associated with cancer, heart disease, stroke, DM, and cognitive dysfunction
Epidemiological Risk Factors for cancer
o Tobacco
o Alcohol
o Lack of fruit and vegetables
o Meat
o Lack of fiber
o Overweight
Chronic inflammation + increased lipids and other macromolecules + insulin signaling + adipokines can lead to cancer
A lot of Leptin is present, which causes chronic inflammation
o Lack of physical exercise
o Post-menopause
o Infections
o Ionizing radiation
o Occupational hazard
o Reproduction
o Sun exposure and sunbeds
o Life style + Carcinogen exposures + Occupational Exposures leads to altered epigenomic marks abnormal expression of tumor-suppressor genes and oncogenes increased susceptibility to cancer
what are the three phases that occur in carcinogenesis process?
- initiation
- promotion
- progression
what is the initiation phase of the carcinogenesis process?
Initiation involves the alteration change, or mutation of genes arising spontaneously or induced by exposure to a carcinogenic agent
Still reversible, Single event mutates the DNA
* Exposure to a known carcinogen- UV light
what is the promotion phase of the carcinogenesis process?
The promotion stage is considered to be a relatively lengthy and reversible process in which actively proliferating pre-neoplastic cells accumulate.
- Within this period the process can be altered by a chemo preventative agents and affect growth rates
clonal expansion of the initiated cell
* constant exposure to that carcinogen substance
can be interrupted and reversed
* smoking
what is the progression phase of the carcinogenesis process?
Progression is the final stage of neoplastic transformation, where genetic and phenotypic changes and cell proliferation occur.
- This involves a fast increase in the tumor size where the cells may undergo further mutation with invasive and metastatic potential
irreversibles
characteristics of benign tumors
- Grow slowly
- Have a well-defined capsule- Encapsulated
- Are not invasive
- Are well differentiated, look like the tissue from which they arose
- low mitotic index, diving cells are rare
- Do NOT metastasize
- NOT cancer
- -oma
o Lipoma, organ hypertrophy
Can be life threatening if enlarged in critical locations - Uniform shape
- Cell cohesiveness
- Controlled growth
- Well-differentiated
- Mortal (apoptosis)
o Programmed cell death if mistakes are found
characteristics of malignant tumors
- Grow rapidly
- Are not encapsulated
- Invade local structures and tissues
- Are poorly differentiated, may not be able to determine tissue of origin
- High mitotic index; many diving cells!!
- Can spread distantly, often through blood vessels and lymphatics (metastasis)
- *Hallmark is anaplasia
o the loss of cellular differentiation, irregularities of the size and shape of the nucleus and the loss of normal tissue structure - Abnormal appearance
- Lack of cohesiveness
- Rapid, disorderly division
- Immortal (lack apoptosis)
what are the two main characteristics that make cancer cells deadly?
1) dont exhibit contact inhibition
2) not anchorage indepedent—>they do not need agar to stick to, they can grow freely
describe cancer cell growth
o abnormal appearance, lack of cohesiveness, rapid disorderly division, poorly differentiated, immortal (lack apoptosis)
describe dysregulated growth
o factor alone does not cause malignancy
o Ability to invade and metastasize are of equal importance
describe anaplasia
o Microscopic hallmark to cancer cells
o Loss of cellular differentiation
**Loss of structural and functional differentiation of normal cells
describe tumor invasion
o capacity for local invasion/spread
Prereq for metastasis
The first step in the metastatic process
Direct tumor extension and then cells migrate way from the primary tumor and invade the surrounding tissues
Mechanisms important to Local Invasion
* Recruitment of macrophages and other cell types to the primary tumor
o There they promote digestion of connective tissue capsules and other structural barriers by secreted proteases
Causes changes in cell to cell adhesion making the cancer cells more slippery and mobile
* changes in the expression of cell adhesion molecules such as cadherins and integrins
o Can be extensive, but may not always involve the vascular and lymphatic entry
Basal cell carcinoma of the skin is an example superficial spread is common and often diagnosed early and treated successfully
o Some tissues are easily invaded, whereas others often resistant to invasion
Difficult to invade include cartilage, tendons, sclera, arterial walls, muscles.
* It is important to consider contractility, density, and antimitotic properties of these tissues
describe tumor metastasis
o Major cause of death from cancer
Cancer that has NOT metastasized, can be cured.
* Steroids are used to reduce the ability of cancer cells to metastasize (inflammation again)
o Ability of malignant tumors (most deadly characteristic) ability to spread far beyond the tissue of origin
o To transition from LOCAL to METASTASIS; The cancer cell must be able to invade local blood and lymphatic vessels
That metastatic cell must be able to survive in the circulation, attach in an appropriate new microenvironment and multiply to produce an entire new tumor
o Complex multistep process
involves the capacity of neoplastic cells to detach from the primary tumor and disseminate to other parts of the body
o Many tumors have begun to metastasize at the time of detection. It is estimated that 60% of patients with solid tumors have microscopic or macroscopic metastasis at diagnosis
what is the seed and soil theory?
Cancer cells (the seed) must overcome multiple physical and physiologic barriers in order to spread, survive, and proliferate in distant locations
The destination (the soil) must be receptive to the growth of the cancer
ONLY certain cancer cells will grow in certain structures
* Must survive 10 diff steps, must win all of them
o There may be many opportunities to interrupt the potential lethal pathway
look on page 4 of objectives for the 10 steps
what does cancer cell secrete in order to spread?
proteases and protease activators
what does active proteases do?
they digest the ECM and basement membranes-> creating pathways which cells can move
define proto-oncogene
o Regulates normal cellular proliferation
o They control cells in the cell cycle!
They basically say get into that cell cycle, and they say get out
Example; growth factor/receptor, RAS
what is RAS
a normal protein that is essential for the cells to go in and out of the cell cycle
what happens when theres a mutation in the RAS gene?
it becomes an oncogene and strong driver to become cancer
define oncogene
o When there is a mutation in a proto-oncogene, they become oncogene
It only takes one mutation to make that transition!
Independent function, acts in a dominant manner
o Oncogene are mutant genes that in their normal non-mutant state direct synthesis of proteins that positively accelerate proliferation
they are GENES THAT CAUSE CANCER
o Drives cells into an unregulated expression of proliferation/uncontrolled cell growth
what is driver mutations? give examples
- They drive the progression to cancer
- Mutations in a coding region
o Example- mutations in p53 or RAS
what is passenger mutations?
- Not all mutations cause cancer, these are random mutations, they don’t mean anything
- A mutation in a “non-coding” region
Mechanisms of Action for Activation of Oncogenes (7)
Point mutations; driver vs passenger
Gene Amplification
* Duplication of a small piece of a chromosome over and over
Chromosomal translocations
* Large changes in chromosome structure in which a piece of one chromosome is connected to another
* *these are more significant, codes for oncogenes
Subtle alterations
* Insertions or deletions
Inversions
Gene silencing
Exogenous sequences (from tumor viruses)
what are tumor suppressor genes?
o regulates the cell cycle, inhibits proliferation, resulting from growth signals, stop cell division when cells are damaged, and prevent mutations
they put the brakes on, PREVENT CANCER in cells!!!
o Also referred as “anti-oncogenes”
o Need TWO mutations before you can get cancer
cancer cells learn to suppress that second allele without needing a mutation
the first one can be turned off by inheritance/environment driven
* tumor suppressor must be inactivated to allow cancer to occur
what are the two main categories of tumor suppressor genes?
-gatekeepers
-caretakers
what are the gatekeepers of TSG?
Give an example
- prevent cells from going through cell cycle, REGULATE cell cycle
- these are checkpoints for errors, prior to going into the cell cycle
o one mutation in a gatekeeper predisposes an individual to cancer, two mutations leads to a neoplasia (excess growth)
example- Rb gene
what are the caretakers of TSG?
- maintain the integrity of cell genetic material
- these protect DNA, maintain the integrity and fix them, help prevent accumulation of mutations
o example- p53
ID chromosomal alterations found in malignancies (4)
-translocation
-deletions
-inversions
-change in chromosome number
what is the key cell that promote tumor survival?
tumor-associated macrophage (TAM)
function of macrophages M1
produces an acute inflammatory response and is responsible for removal and destruction of infectious agents
function of macrophages M2
produces inflammatory mediators to suppress ongoing inflammation and induce cellular proliferation, angiogenesis, and wound healing
TAM mimic M2
how does TAM evades/avoids immune destruction?
o TAMs have diminished cytotoxic response, and develop the capacity to block T-cytotoxic cell and NK-cell functions and produce cytokines that are advantageous for tumor growth and spread.
o TAMs secrete cellular growth factors, that favor tumor cell proliferation, angiogenesis, and tissue remodeling, similar to their activities in wound healing
Mechanisms by Which Tumor Cells Evade the Immune System
o Tumors may evade the immune response by losing expression of antigens or major histocompatibility complex (MHC) molecules or by producing immunosuppressive cytokines or ligands for inhibitory receptors on T cells
- Restricting antigen recognition, inhibiting immune system, and reducing T cell exhaustion
o Viral and tumor antigens are processed by the tumor cells and presented on the cell surface by MHC class I molecules and are targets of CD8+ T-cytotoxic cells
o the theory of inflammation suggests that a variety of infectious mediators and their relationships with inflammatory cells are a major cause of cancer.
Define carcinoma in situ (CIS)
o Pre-invasive epithelial tumors of glandular or squamous cell origin
o Early stage cancers are localized to the epithelium and have NOT penetrated the local basement membrane or invaded surrounding stroma
changes are occurring but has not invaded basement membrane
o Not malignant therefore they are called CIS
Steps to prevent; SCREENING AND SURVEILLANCE!!
what three fates do CIS lesions have?
Can remain stable for a long time
Can progress to invasive and metastatic cancers
Can regress and disappear
treatment for CIS
Challenging due to unknown if it will progress to cancer
Some people prefer “removal” vs watchful waiting
SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: Angiogenesis/Neovascularization
o When we have a cut or a wound, healing is the process of establishing new blood vessels within the tissue to undergo repair.
Once the tumor begins to grow larger than a mm in diameter, they NEED their own blood supply to deliver oxygen and nutrients
o Normally- angiogenetic factors/angiogenic inhibitors
Control development of new vessels
o In Cancer
Several mechanisms increase and maintain secretion of angiogenetic factors
* Vascular endothelial growth factor (VEGF)
* Platelet derived growth factor (PDGF)
* Basic fibroblast growth factor (bFGF)
All three ^^ recruit new vascular endothelial cells and initiate the proliferation of existing blood vessels in cells, ALLOWING SMALL CANCERS TO BECOME LARGE ONES- feeding the tumor
SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: Energy Metabolism
o Cancer cells often grow in a hypoxic/acidic environment
o Alteration in a number of cancer genes promote the activity of glycolytic (breaking down sugar to generate energy) pathways that support growth of cancers – in other words they uptake sugar!!!
^This is why with PET scans, cancer can be detected!
SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: resting apoptosis
o Normally- apoptosis, a programmed cell death that is triggered by either intrinsic pathway (mitochondrial) or the extrinsic pathway
o Cancer- turned off
P53 gene mutations
describe warburg effect
4 ATP/glucose is produced
Cancer cells utilize glucose and pyruvate to generate lactate
Cancers Have Altered Metabolism Normal tissues use oxidative phosphorylation (OXPHOS) to turn glucose into CO2 and energy (in the form of ATP) Cancers take a different approach; even in the presence of oxygen, usually they do not use OXPHOS. Instead, they consume large quantities of glucose to make cellular building blocks, supporting rapid proliferation.
what are tumor markers and why is it important?
- Substances produced by both benign and malignant cells, are either present in or on tumor cells or are found in blood, spinal fluid, urine
o Tumor markers- Include hormones, enzymes, genes, antigens, and antibodies - Tumor markers are important because a lot of cancer cells can produce a lot of substances that mimics normal biologic substances
how are tumor markers used? (3)
o Screen and identify individuals at high risk for cancer
o Help diagnose the specific type of tumor in patients with clinical manifestations relating to their tumor
Adrenal tumor, enlarged liver, or prostate
o Follow the course of a tumor
T-N-M staging classification
it is a classification staging system for cancers-solid organ
o T: the size and/or extent (reach) of the primary tumor
Indicates tumor size
o N: amount of nearby lymph nodes
Indicates node involvement
o M: presence of metastasis or secondary tumors formed by the spread of cancer cells to other parts of the body
Indicates the presence of distant metastasis
staging cancers
o Stage 1- cancer confine to the organ of origin (cancer in situ)
o Stage 2- cancer that is locally invasive
o Stage 3- cancer that has spread to regional structures, such as lymph nodes
o Stage 4- cancer that has spread to the distant sites
Liver spreading to lung or prostate spreading to bone
Ann Arbor Staging System for NHL- liquid tumor staging
o Stage 1- single lymph node/extralymphatic site
o Stage 2- two or more lymph node regions on the SAME side of diaphragm
o Stage 3- lymph node involvement to BOTH sides of the diaphragm
o Stage 4- diffuse extralymphatic disease
discuss tumor grading in relation to cell differentiation
- Grade VERY different than staging!
o Grading is- how differentiated cells are
o Used to target treatment - Tumor grade describes a tumor based on how abnormal the cells and tissue look to indicate how quickly a tumor is likely to grow and spread
- Tumor grading determines how responsive the disease will be to therapy
Grading System for tumors that are NOT SPECIFIED
o 1-4 depending on abnormality
G1- well differentiated (low grade)
G 2- moderately differentiated (intermediate grade)
G 3- poorly differentiated (high grade)
G 4- undifferentiated (high grade)
o Grade 1- Tumor cells and the organization of the tumor tissue appear close to normal
o Grade 3 and 4- tumors do not look like normal cells.
Grade 3 and 4 grow rapidly and spread faster
IDENTIFY PARANEOPLASTIC SYNDROMES AND LINK THEM TO PATHOPHYSIOLOGIC MECHANISMS OF CANCER
o Symptom developments that are triggered by a cancer but are not caused by direct local effects of the tumor mass
o Mostly caused by biologic substances that are released from the tumor or by the immune response triggered by the tumor, hormones!
Example- carcinoid tumors release serotonin into the bloodstream, causing flushing, diarrhea, wheezing, rapid heartrate
Usually occur at distant sites of primary tumor
* Endocrine, neuromuscular, renal, hematologic, cardiovascular, musculoskeletal, GI, rheumatologic systems autoimmune triggered
o These syndromes are significant because they may be the earliest symptom of an unknown cancer**
what is Rb protein (pRB) responsible for?
its responsible for a major G1 checkpoint, blocking S- phase entry and cell growth
- it is also a tumor suppressor gene
-plays a important role in the negative control of the cell cycle and in tumor progression
