Day 3- Cancer (Patho)

Question 1

What are 3 modes/ mechanisms that cancer can travel?

Answer 1

~Bloodstream (hematogenous or vascular)
~Lymphatics
~Direct extension into neighboring tissues

Question 2

How can the cancer grow to the neighboring tissues?

Answer 2

*The cells will just keep growing/ dividing until it gets to the neighboring tissues

~Local invasion and tumor angiogenesis
~Venous drainage and further spread via metastatic cascade
~“skip metastasis” – bypass local lymph and form distant nodal mets

Question 3

Are there normal patterns that metastatic of cancer will follow?

Answer 3

Yes

Question 4

What determines the normal metastatic pattern of cancer?

Answer 4

Patterns of regional venous drainage, blood flow, and lymphatics determine common metastatic patterns

**there’s a huge table in the book on the primary cancer, mode of dissemination, and location of mets (just if you are interested- Table 13-4)

Question 5

What is an example of metastatic patterns of cancer?

Answer 5

~breast cancer spreads via lymphatics and vertebral venous system to bones in shoulder, hip, ribs, vertebrae, lungs, liver

Question 6

Why should the doctor be careful when resecting a tumor?

Answer 6

If the tumor does not have clear margins when resected, mets can occur. new blood vessels with form during the healing process from resection

Question 7

What is benign mechanical transport?

Answer 7

~lymphatic transport of epithelial cells displaced by biopsy of basic tumor

*breast massage-assisted sentinel lymph node (SLN) localization can cause the tumor to dislodge- resulting in benign mechanical transport

Question 8

What are all cancers characterized by?

Answer 8

~Unregulated growth

~Invasion and spread of cells from the original site to other sites - metastasis

Question 9

Up to 70% of autopsies of patients who died of cancer showed….

Answer 9

spinal metastases

Question 10

Metaplasia

Answer 10

~replacement of one differentiated cell type with another mature differentiated cell type.
~Not malignant
~the basal cells (epithelium stem cells) switch to making another cell type, usually in response to some stress (think metaplasia of bronchial epithelium in a smoker)
~dysplasia can easily follow

Question 11

Dysplasia

Answer 11

~expansion of immature cells with decrease in the number and location of mature cells
~usually signals a pre-cancerous process

Question 12

Hyperplasia

Answer 12

~increased number of cells, which may or may not signal a pre-cancerous or cancerous process
~may be very benign, such as a callous

Question 13

Neoplasia

Answer 13

~“new growth”

~may be benign or malignant

Question 14

What are the 3 basic processes in which our body regulates cells?

Answer 14

~Cell division
~Cell differentiation
~Apoptosis

Question 15

Where in the normal processes can a problem occur?

Answer 15

ANYWHERE!

Cellular mutations can affect any of these processes, producing abnormalities in cell numbers

Question 16

What are the steps for metastasis of cancer cells?

Answer 16

~Primary tumor
~Localized invasion
~Intravasation
~Transportation thru the Circulatory System
~Arrest in microvasculature of organs
~Extravasation

Question 17

What does Intravasation mean?

Answer 17

the entrance of foreign matter into a vessel of the body and especially a blood vessel

Question 18

What does Extravasation mean?

Answer 18

the escape from a vessel into a tissue

Question 19

More details on the steps for metastasis of cancer cells

Answer 19

~Spread of tumor within the tissue of origin through local invasion of tissue

~Spread into micro-vascular by intravasation

~Circulates through the vascular before being trapped in the microvasculature of other organs

~Tumor cells then extravasate into the other organs to form a secondary tumor

Question 20

What are the 6 hallmarks of cancer?

Answer 20

~Evading apoptosis
~Self-sufficiency in growth signals
~Insensitivity to anti-growth signals
~Tissue invasion & metastasis
~Limitless replicative potential
~Sustained angiogenesis

Question 21

growth and division requires

*Nice to know- not on exam

Answer 21

external growth factors (GFs)

**I will put- “nice to know- not on exam” in the parts where she said it; I’m guessing she meant it for a good bit of this section, but I will put it in where she said it.

Question 22

Growth Factors (GFs)

*Nice to know- not on exam

Answer 22

~Diffusible, produced by other cells & bind to cell receptors
~Trigger intracellular kinases which in turn triggers cell division

Question 23

Abnormality of growth in cancer cells occurs when:

*Nice to know- not on exam

Answer 23

~Too many receptors & over-stimulation of growth
~Self production & release of GFs which stimulate growth
~Trigger may be genetic, environmental

*she wants us to know that a trigger makes the growth increase

Question 24

What are oncogenes?

Answer 24

~Small segments of DNA which can transform normal cells into malignant ones
~Activated from “normal” proto-oncogenes by a mutation

Question 25

What happens when cells stop listening to each other? *Nice to know- not on exam

Answer 25

Cancer cells don't respond to signals and keep dividing over normal cells that have stopped growing

Question 26

In normal growth and division, cells are signaled to stop with .... *Nice to know- not on exam

Answer 26

anti-growth signals from other cells which include: ~Soluble growth factors ~Immobilized inhibitors embedded in the extracellular matrix ~Immobilized inhibitors on the surfaces of nearby cells

Question 27

In normal cells, how is the growth checked? *Nice to know- not on exam

Answer 27

the cell responds to antigrowth signals associated with the G1 checkpoint of the cell growth cycle

Question 28

What are the phases in the cell cycle? *Nice to know- not on exam

Answer 28

``` ~G0 ~G1 ~S ~G2 ~M ```

Question 29

What is G0 phase *Nice to know- not on exam

Answer 29

resting phase where the cell has left the cycle and has stopped dividing

Question 30

What is G1 phase *Nice to know- not on exam

Answer 30

cell growth in preparation for increased DNA synthesis **G1 checkpoint is a regulatory step preventing move into DNA synthesis phase thus preventing cell division

Question 31

What is S phase *Nice to know- not on exam

Answer 31

DNA synthesis phase

Question 32

What is G2 phase *Nice to know- not on exam

Answer 32

cell growth preceding mitosis

Question 33

What is M phase *Nice to know- not on exam

Answer 33

mitosis, cell division

Question 34

What does nectins and nectin-like substances do in normal cells?

Answer 34

~play a role in contact inhibition – prevention of mitosis once cells of a tissue come in contact with one another ~play a role in limiting the movement of cells – cell motility

Question 35

What does nectins and nectin-like substances do in cancer cells?

Answer 35

~Nectins & nectin-like substances may be deficient so that there is a lack of normal contact inhibition and an overgrowth of cancer cells ~Deficit of nectins & nectin-like substances may produce the excessive cell movement of cancer cells and spread of cells that begins metastasis

Question 36

What is another name for anti-oncogenes?

Answer 36

tumor suppressor genes

Question 37

What do anti-oncogenes do?

Answer 37

~Can regulate growth and inhibit carcinogenesis ~Genes that when active decrease risk of a cell becoming metastatic (cancerous) ~Code for proteins

Question 38

In anti-oncogenes, the can code proteins. What does this do?

Answer 38

~Have a repressive effect on progression thru the cell cycle ~Promote apoptosis ~Do both

Question 39

P53 Tumor Suppressor Gene | is nicknamed...

Answer 39

“The Guardian of the Genome”

Question 40

P53 Tumor Suppressor Gene

Answer 40

~forms P53 protein, which changes gene expression to halt cell proliferation & trigger apoptosis when DNA is damaged ~Halts cell division in G1 phase in response to DNA damage ~Destroys potentially malignant cells via apoptosis ~Found to be mutated or otherwise disrupted in the majority of all types of cancers

Question 41

Cancer cells and apoptosis

Answer 41

~Normal cells are programmed to die at a certain point | ~cancer cells keep going (don't die)

Question 42

Apoptosis occurs in a precisely choreographed series of steps: *Nice to know- not going to be on exam

Answer 42

Cellular membranes are disrupted, the cytoplasmic and nuclear skeletons are broken down Cytosol is extruded Chromosomes are degraded, and the nucleus is fragmented Shriveled cell corpse is engulfed by macrophages & disappear in 24 hours

Question 43

What are the two components of apoptosis?

Answer 43

~sensors | ~effectors

Question 44

What are sensors?

Answer 44

~Cell surface receptors that bind survival or death factors such as: IGF, Interleukins, TNF-alpha & FAS (in TNF family) ~Internal sensors of DNA damage or other abnormality stimulate the release of effector agents

Question 45

What are effectors?

Answer 45

Stimulated by abnormality sensors, the mitochondria release chemicals to trigger apoptosis

Question 46

Example of cancer evading apoptosis:

Answer 46

~Lymphoma-related oncogenes depressing the FAS death signaling circuit ~Mutation of p53 tumor suppressor gene

Question 47

Self-Building Vascular Supply

Answer 47

~Tissue survival requires nutrients & oxygen from blood ~Cells stop growing if they are any greater than a certain distance from a source of oxygen & nutrients ~P53 suppression allows mutation and proliferation

Question 48

Vascular Supply and Cancer cells

Answer 48

Cancer cells have the unique ability to signal the growth of new blood vessels to themselves to sustain growth (using VEGF, vascular endothelial growth factor)

Question 49

Vessel Anatomy

Answer 49

~Normal architecture of vasculature is highly organized ~Abnormal architecture with tumor vasculature is highly disorganized ~Vessels are tortuous and dilated with uneven diameter, excessive branching and shunts ~Numerous endothelial fenestrae, vesicles and transcellular holes, widened inter-endothelial junctions, and a discontinuous or absent basilar membrane ~All of these changes result in high vessel permeability and promote metastasis

Question 50

Examples of chemotherapy agents that target angiogenesis:

Answer 50

~Blocking VEGF receptor (Bevacizumab) ~Interfering with tyrosine kinase (Sunitinib & Sorafenib) ~Interfering with intracellular activator pathways (Sorafenib)

Question 51

Compare normal cells, benign tumors, and malignant tumors- boundaries

Answer 51

~Every normal tissue has boundaries ~Benign tumors don't cross into other tissues, merely pressing against them ~Malignant tumors spread and invade into other tissues ~Cancer cells can break off too, spreading "seeds" around to other parts of the body (“soil”), which grow into new tumors ~90% of cancer deaths come from metastases

Question 52

Metastasizing cells must do what 3 things

Answer 52

~Intravasate into the vasculature ~Stop in the microvasculature of the invaded tissue ~Extravasate into the invaded tissue from the vasculature

Question 53

Details about Metastasizing cells must adapt to new environments

Answer 53

~Adaption of cellular membrane proteins ~Intercellular signaling ~Changes from one configuration to another in different environments ~Certain cellular environments are conductive to particular tumor growth and others are not – one explanation for selective metastasis (why metastasis occurs in some tissues but not in others with certain cancers)

Question 54

What is the hayflick limit?

Answer 54

~Aside from being programmed to die, all cells have a limit to how many times they can divide before they cannot divide any more ~Cancer cells have unlimited dividing potential ~They never stop dividing ~They are true immortal cells ~Normal human fetal cells in a cell culture divide between 40 and 60 times ~Cells then enter a senescence phase and stop ~Cell reproduction with physical age as well ~Each mitosis shortens the telomeres on the DNA of the cell ~Telomere shortening in humans eventually makes cell division impossible, and correlates with aging **Easier to understand: The concept states that a normal human cell can only replicate and divide forty to sixty times before it cannot divide anymore, and will break down by programmed cell death or apoptosis. (there's a limit to how many times the cell can divide.)

Question 55

What is a telomere?

Answer 55

~Region of repetitive DNA sequences at the end of a chromosome ~Protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes

Question 56

What would happen without telomeres?

Answer 56

~Without telomeres, cells would lose the ends of their chromosomes at cell division, and the information they contain ~Telomeres are disposable buffers blocking the ends of the chromosomes & are consumed during cell division

Question 57

What is a TERT?

Answer 57

telomeres replenished by the enzyme telomerase reverse transcriptase (TERT)

Question 58

What do TERTs do?

Answer 58

~TERT needed to extend lifespans of certain cells such as fetal stem cells ~TERT activation has been observed in > 90% of all human tumors ~the immortality conferred by telomerase plays a key role in cancer development

Question 59

Limitless reproductive potential due to what two things?

Answer 59

~loss of cell cycle checkpoints | ~role of telomerase

Question 60

What s the 7th characteristic of cancer?

Answer 60

genetic instability

Question 61

Genetics and cancer

Answer 61

~Cancer is the result of genetic changes to the cell | ~Cancer requires an accumulation of mutations, creating a progression from a healthy cell to a malignant cell

Question 62

types of mutations that can result in cancer

Answer 62

~Changes in single bases ~Insertion of individual bases or sequence ~Chromosome translocations ~Chromosome deletions

Question 63

Inherited genetic instability

Answer 63

~present at birth and in every cell ~passed from one generation to the next ~increase the risk of cancer exponentially ~are found in many familial syndromes

Question 64

somatic genetic instability

Answer 64

~acquired throughout life in individual cells ~not passes on to the next generation ~increased risk of cancer but less so ~not associated with familial syndromes

Question 65

Some familial syndromes known to increase cancer risk:

Answer 65

~BRCA1 and BRCA2

Question 66

BRCA1 and BRCA2

Answer 66

~BRCA1 and BRCA2 are expressed in the cells of breast and other tissues, where they helps repair damaged DNA, or destroy cells if DNA cannot be repaired ~Function as tumor suppressor proteins ~Absence or mutation of these proteins risk for breast and ovarian cancer, which can be inherited – called a “founder” effect

Question 67

BRCA2 mutation:

Answer 67

~risk for leukemia also reported ~Example of “founder” mutation is found in Iceland, where a single BRCA2 mutation accounts for virtually all breast/ovarian cancer families ~A large study in the US **BRCA2 mutation found in 0.6% of the population **72% of patients who were found to be carriers had a moderate or strong family history of breast cancer

Question 68

Stats with BRCA1 or BRCA2 mutation:

Answer 68

~Women with an abnormal BRCA1 or BRCA2 gene have up to a 60% risk of developing breast cancer ~28% of hereditary breast cancer is caused by BRCA1 mutations ~19%of hereditary breast cancer is caused by BRCA2 mutations ~increase risk of developing ovarian cancer **55% for BRCA1 **25% for BRCA2