Cancer

Question 1

Cancer

Abnormality in cell _____, ______, and/or cell _________

A disruption of cellular _______

A disruption in the normal functioning of _____ ______ genes =

• Cells in our body are under a tremendous amount of ______ - a fascist society
• Cancer is a ______ of those genes

Answer 1

growth, division, differentiation

cellular societies

social control genes any gene that codes for a protein that is involved in cell growth, divsision, and differentiation

• control
• disruption

Question 2

Social Control Genes

direct, stimulate, inhibit, or regulate

(6)

Answer 2

Cell Division

Cell Differentiation

Cell Growth

DNA repair

Cell mortality (# of times a cell can divide)

Apoptosis (programmed cell death/suicide)

Question 3

Four Phases of Pathogenesis and Spread

(4)

Answer 3

Transformation

Growth of Transformed Cell

Local Invasion

Distant Metastasis

Question 4

Transformation

=

Growth of Transformed Cell

=

Answer 4

Altered growth-proliferation control (on genetic level) - normal host cell transforms into a malignant cell (oncogene) from a mutation in a social control gene (not every mutation is going to produce cancer, transformation of cells is not uncommon but the continued growth is fairly uncommon, immune system usually kills it

Tumor formation - proliferation of malignant cells into a tumor

Question 5

Local Invasion

=

Distant Metastasis

=

Direct extension Metastasis

Answer 5

Invade surrounding tissue and creation of own blood supply (cancer cells will not just invade but eats a hole through whatever it encounters)

Cells break free from tumor colonize distant sites

Same tumor just grows into a neighboring organ

Question 6

The Cell Cycle-Phases of Cell Division

1. G1:
2. S:
3. G2:
4. Mitosis:

Answer 6

1. Cells are getting ready for DNA replication (most cells in this stage)
2. Cells actively replicating DNA
3. Cells making copy of its intracellular material and proteins - final phase before cellular division
4. Cellular division (starts with nuclear division and ends with cytoplasm division)

Question 7

Common Targets of Potential Mutations

• Cell Cycle Inhibitors =
  
  • ​Some of these really powerful inhibitors (1) are the common genes mutated in cancer -> don’t get tonic inhibition
• DNA repair proteins =
  
  • ​(2) examples that if mutated dramatically increases lifetime risk of (3) types of cancer -> at the heart of it is all about the loss of DNA repair

Answer 7

• like breaks at every stage that prevents cell from moving onto next phase, the genes that code from them are notoriously oncogenes
  
  • Master breaks (doors with triple locks)
• Designed to identify potential mutations, can sometimes repair it themselves or trigger apoptosis if too many errors detected
  
  • BRCA 1/BRCA 2, breast, uterine, ovarian

Increased risk for mutuation leading to malignancy with more cell division/replication

Question 8

Phases of Mitosis

What phases of Mitosis of the cell cycle are the easiest to visually identify histologically? Why?

• Takeaway: you _____ see normal cells in any phase of mitosis, most cells are in the ___ phase
• Rate of cell division: # of cells in active division is part of assessment of how _______ the cancer can be
• Nondividing cells (2): are all strongly frozen in the ___ phase
  
  • Ex) Brain tumors are never of ______ origin, usually ____ cells

Answer 8

Metaphase (chromosomes being lined up) and Anaphase (chromosomes pulling apart) -> patholgist can see alot of cells are in active mitosis in tumors

• rarely, G1
• aggressive
• neuronal, myocytes, G0
  
  • neuronal, glial (glioma, astrocytoma)

Question 9

Cell Differentiation

• With every differentiation step
  
  1. Fate of the cell _____
  2. _____ activity starts to _____
• Terminally differentiated cell =
  
  • ​Ex) ______ ______ cells: terminally differentiated cannot handle damage from smoking and get replaced by newly differentiated simple squamous so now you lose cilia that helps to clear mucus and you get a cough and mucus buildup ​

Answer 9

• With every differentiation step
  
  1. narrows
  2. Mitotic activity declines
• most functionally mature and lost it’s ability to divide
  
  • Ciliated Columnar Cells

Example of differentiation. Differentiation occurs several times in the lifetime of a granulocyte, with each step further limiting the cell’s potential. Eventually the cell terminally differentiates and can no longer divide, and the mature cells die.

Question 10

Cancer Cells Resist Differentiation

• ____ differentiated tumor cells = more aggressive cancer bc very ______ active and contribute least to the _____ of the tissue and create more problems for the pt
  
  • ​Ex) ______ = over-proliferation of highly undifferentiated rbcs, wbcs -> anemia, immunodeficiency bc wbc are malignant and don’t work

Answer 10

• Less differentiated = more aggressive, mitotically active, contributes least to function
  
  • Leukemia

Question 11

Cell Differentiation

• Normally, stem cells first divide then?
  
  • What happens in the pattern of potential tumor formation?
  • What is a common cell type to become cancerous bc it is rapidly dividing all the time?
• Characteristics of Malignant cells
  
  1. ​____ rate of unregulated cell ______
  2. ______ to differentiation

Answer 11

• half of the daughter cells will go on to differentiate
  
  • When more than half of stem cells remain stem cells and refuse to differentiate
  • Epithelial tissue
• Characteristics of Malignant cells
  
  1. ​​High rate of unregulated cell division
  2. Resistance to differentiation

Differentiation of a stem cell. A, When a stem cell divides, each daughter has a choice: it can either remain a stem cell or go on to become terminally differentiated. B, this pattern of cell renewal and proliferation of stem cells in the epithelium forms the lining of the small intestine

Question 12

Cancer Cells

The transformation of a cell into a cancer cell involves a mutation in a ______ ______ gene to form an ______.

1. ​(1) = promotes normal cell division or growth
   
   • Mutation causes ______ of gene ->Oncogene -> promotes cancerous cell growth
2. (1) = limits normal cell division/growth or promotes cell differentiation/cell death
   
   • Mutation causes _____ of gene -> Oncogene ->promotes cancerous cell growth

• Nearly every hereditary cancer is linked to what type of gene?

Answer 12

mutation in social control gene ->oncogene

1. Proto-oncogene
   
   1. Hyperactivity (turned on to promote cell division through growth factors and cytokines)
2. Tumor-suppressor gene
   
   1. ​Inactivity (ie BRCA 1/2 so can’t limit formation)

• Tumor suppressor gene

Question 13

Two Routes of Mutations that produce Oncogenes (notes)

1. (1): purple side - growth factors, receptor for growth factors, inside the cell has intracellular signaling proteins, and transcription factors that the growth factors work through
2. (1): blue side - cell cycle inhibitor or potentially a cell differentiation stimulator- has receptors and intracellular signaling proteins, and transcription factors

• Wide variety of potential targets for development of proto-oncogenes for these growth factors and tumor suppressor genes

Answer 13

1. Stimulatory Route
2. Inhibitory Route

Question 14

Pathways of Mutation

Genetic mutations can cause cancer. Genetic mutations cause ______ pathways (purple) to tissue too many “__ signals” or ______ pathways (blue) can no longer issue “___ signals”.

A stimulatory pathway will become _____ if a mutation (ie. oncogene) causes any component, such as a ____ factor receptor (box at left) to issue stimulatory messages autonomously without waiting for signals from upstream. Conversely, _____ pathways (e.g., mutations causing tumor-suppressor genes) will be shot ____ when some constituent, such as cytoplasmic relay (box at right), is eliminated and thus _____ the signaling chain

Answer 14

stimulatory, “go signals”, inhibitory “stop signals”

hyperactive, growth

inhibitory, shot down, breaks the signaling chain

Question 15

Mechanisms for Abnormality-Targets of Oncogenes

Aspects of cell function under social control and therefore possible mechanisms for cancer disruption

1. _____ transduction
2. Cell _____ control
3. DNA _____
4. Cell ____
5. Cell _______
6. ________ regulation
7. S_____
8. A_______

Answer 15

1. Signal transduction
2. Cell cycle control
3. DNA repair
4. Cell growth
5. Cell differentiation
6. Transcriptional regulaiton
7. Senescence
8. Apoptosis

Question 16

Targets of Oncogenes

• Cell Cycle Control =
• Transcription factors =
• Senescence =
  
  • ​Immortalized cell =

Answer 16

• cell cycle inhibitors or stimulators that are potential targets
• proteins that control whether a gene gets expressed or not (they are inside the nucleus at the lvl of DNA and bind to promoter regions of a gene to determine whether it gets transcribed or not)
• the limit that any cell in our body has to the number of cell divisions it can undergo (usually about 50-60 times) - its mortality
  
  • ​when they continue to divide past beyond that point - capable of passing on genome in an unlimited way

Question 17

Known Proto-Oncogenes and Tumor Suppressor Genes

3 important/common tumor suppressor genes

1. P53 protein =
2. RB protein =
3. DNA repair protein (2)

• Subcellular location and functions of major classes of cancer associated genes
  
  • red =
  • blue =
  • green =
  • purple =

Answer 17

1. coded by p53 gene and expression of P53 also increases as the number of errors on DNA are identified by the cell -> inhibition of cell cycle gets stronger as the cell notices ore errors on DNA -> once amount of p53 hits a critical point -> triggers apoptosis
   
   • ​Half of all tumors have mutations in P53 gene
2. coded for RB gene, stands for retinoblastoma bc first identified in that cancer type, also a common mutation in all types of tumors, a massive cell cycle regulator (doors in the cell cycle) if mutated will free the cell to divide as much as it wants
3. BRCA 1/2

• proto-oncogenes (normal genes that regulat growth and differentiation)
• cancer suppressor genes
• DNA repair
• genes that regulate Apoptosis

Question 18

Basic Properties/Behaviors of Cancer Cells

Autonomy and Anaplasia

1. (1) Cancer cells _____ despite lack of _____-initiating signals from the environment
2. Cancer cells _____ signals to die (turn off signals for apoptosis) and achieve a kind of ______ in that they are capable of unlimited ______
3. (1)Cancer cells lose their _______ features and contribute poorly or not at all to the _____ of their tissue
4. Cancers cells are _______ unstable and evolve by accumulating new ______ at a much faster _____ than normal cells
5. Cancer cells ____ their local _____ and _____ their neigbors

Answer 18

1. Autonomy: proliferate, despite lack of growth initiating signals
2. escape signals, immortality, unlimited replication
3. Anaplasia: lose differentiated features, contibute poorly to function
4. genetically unstable, accumulate mutations, faster rate
5. invade local tissue, overrun their neighbors

Question 19

Cell Mortality and Senescence

Normally cells can divide (double) about __-__ times before growth shuts off (1)

->

Some escape (1) and keep dividing. Eventually these cells will reach (1) and start dying off in large numbers

->

Cells that manage to escape Senescence and Crisis have acquired some _____ that has (1) them

Answer 19

50-60 times (Senescence)

Senescence, Crisis

mutatio, Immortalized

Question 20

Telomeres

=

Everytime DNA replicates, telomeres get?

Answer 20

Like the plastic tips on shoelaces, without it ends of DNA would separate and fray and become vulnerable to mutation

Shorter

Question 21

Telomerase Enzyme

=

What happens to the telomerase enzyme over time?

Answer 21

Function is to rebuild telomeres

A cell’s ability to produce telomerase progressively declines with greater # of cell divisions -> finally can’t rebuild telomeres -> errors accumulate along terminal protions of that DNA -> DNA repair proteins will bind to those errors and block cell division = senescence

Question 22

Control of Replication

• So for cells that escape senescence -> continue to multiply and all of those daughter cells have lots of _____
• One protein that starts to get expressed when the cell finds errors (1) -> then when there’s enough of this P53 -> _____ = ______
• So if there’s a problem w P53 or DNA repair it can also become ______
• Ans: Cell’s ability to overexpress telomerase enzyme = can in an unlimated way keep repairing its telomeres and continue to double = ____-_____

Answer 22

• errors
• P53 -> Apoptosis = Crisis
• immortalized
• Proto-Oncogene

Question 23

Structural and Functional Changes in Cancer Cells

(4)-(2)

Answer 23

Cytoskeletal Changes

Changes in Cell Adhesion/Motility

• Role of Fibronectin
• Implication for Density dependent growth

Nuclear Changes

Enzyme Production

Note: CEA = carcinoembryonic antigen, AFP = alpha-fetoprotein

Question 24

Cytoskeleton Changes in Malignant Cells

=

Answer 24

Amorphous, globular, irregular shape dt disorganized cytoskeleton

Gets disassembled when the cell mitotically divides and cancer cells have high mitotic rates

Question 25

Nucleus Changes in Malignant Cells =

Answer 25

Disorganized/amorphous shape again dt high mitotic rates Chromatin and chromosomes are unwinding and are in some stage of DNA replication and division

Question 26

Cell Adhesion Molecules in Normal Cells ## Footnote **Fibronectin =** **Density Dependent Growth =**

Answer 26

normal cell adhesion molecules that anchor one cel to the neighboring cell -\> helps maintain the integrity of tissue and regulates density dependent growth By being physically connected to your neighbors, you know how many neighbors you have which tells you the density of that tissue and when it reaches optimal cell density -\> will shut off replication and division

Question 27

Cell Adhesion Molecules in Malignant Cells = * How does this effect their growth? * How does it effect their spread? * Ex (1)

Answer 27

Cancer cells often lack adhesion molecules including fibronectin * Don't care what the density of the tissue is, does not control their growth * Also means that cancer cells are not anchored to one another and makes them more **mobile** -\> can shed off of a tumor * Ovarian CA most commonly from the external epithelial lining of the ovaries so the way they spread is just by falling off into pelvic cavity (only symptoms will be bloating/pain and not found till later stages)

Question 28

Enzyme Production in Malignant Cells =

Answer 28

Cancer Cells have ability to release **lysosomal enzymes** and degrade surrounding tissue -\> eat their way through tissue, invade lymphatic and blood vessels * Cytoskeleton and Nucleus changes mostly abut being mitotically active * Lack of cell adhesion and ability to increase production of lysosomal enzymes common mutations of malignant cells that allow it to spread

Question 29

Routes of Mutagenesis (4)-(2)

Answer 29

**Gene-Environment Interaction** **Inherited Cancer Genes** **Oncogenic Viruses** * **Direct Mutagenesis** * **Indirect Mutagenesis** **Oncogenic Bacteria**

Question 30

Gene Environment Interaction ## Footnote Most ____ route of mutagenesis from _____ (ionizing radiation, tobacco smoke, UV light) * Japanese women higher stomach cancer risk, US women higher breast cancer risk and if we swtich the two, their risks also switch to their environment but we don't know what the carcinogen is

Answer 30

Most common route from **Carcinogens**

Question 31

Inherited Cancer Genes ## Footnote Not as common, under alot of investigation bc if we can identify the gene we can _____ for it and prevent cancer (BRCA 1 and 2) Nearly every inherited cancer stems from an inherited **(1) gene**

Answer 31

SCREEN ## Footnote **tumor suppressor genes**

Question 32

Oncogenic Viruses ## Footnote **Direct Mutagenesis =** * Example (1) **Indirect Mutagenesis =** * Example (1)

Answer 32

When a virus infects a specific tissue bed, gets inside the cells and use it to replicate the virus -\> viruses that in the process of infecting the host cell inserts an oncogene into the host cells genome and gets propagated, transforms cell into a cancer cell * HPV Virus infects and attacks a tissue bed and contributes to a lack of immune regulation that would normally catch a mutation -\> so viral infection is preventing immune system from being able to recognize transformed malignant cells * Kaposi Sarcoma in AIDS

Question 33

Oncogenic Bacteria = Ex (1)

Answer 33

Bacteria that infect tissue fro a prolonged period of time and as a result increases risk of developing cancer **H. Pylori** (bacteria found in digestive tract, increases risk for PUD, bc does not cause a lot of cell injury will not trigger a huge immune response but will cause chronic inflammation -\> chronic injury -\> chronic cell turnover and risk of mutation -\> vulnerable to development of stomach carcinomas

Question 34

Transformation by Altered Genetic Changes ## Footnote Stimulus (initiator) causes genetic mutation (oncogenes and tumor suppressor genes) -\> Altered genes for * ______ factors * _____ factor receptors * Signal communication (t\_\_\_\_\_) * T\_\_\_\_\_ regulation Transformed cell proliferates with abnormal and ______ regulation of growth as a result of genetic changes -\> Tumor

Answer 34

* Growth factors * Growth factor receptors * Transduction * Transcription autonomous

Question 35

Cancer Grade ## Footnote **The degree of \_\_\_\_\_\_** **\_\_\_\_\_\_\_\_ (cell turnover, degree of anaplasia, etc)** * Done through examination of tumor cells (\_\_\_\_\_\_), cells are visually examined and given a grade that reflects their degree of malignancy/how aggressive this cancer is * High grade = * Low grade = * Aggressive = more potential for \_\_\_\_\_\_

Answer 35

**Malignancy** **Aggressiveness** * biopsy * more aggressive, high cell turnover, undifferentiated * less aggressive, slow cell turnover, more differentiated * spread

Question 36

Cancer Stage ## Footnote **Degree of \_\_\_\_\_\_** **"Stage" in disease \_\_\_\_\_\_\_** * What stage in the spread of this cancer is the pt in (diff cancers have diff staging schemes bc they spread through diff patterns) * Stage IV across the board considered _____ cancer -\> ______ treatment

Answer 36

**Spread** **progression** terminal cancer -\> palliative treatment

Question 37

Benign Tumor ## Footnote = \_\_\_invasive and doesn't have potential for rapid \_\_\_\_, ___ aggressive - usually just an _____ of ____ tissue * Often fully _______ and doesn't ____ surrounding tissue, just ______ it * Ex) Uterine \_\_\_\_\_, picture is a classic \_\_\_\_\_

Answer 37

= noninvasive and doesn't have potential rapid spread, not aggressive, usually just an overgrowth of original type * encapsulated, does not invade, just displaces * fibroids, lipoma

Question 38

Malignant Tumor ## Footnote = ______ borders, has eaten away to the skin (\_\_\_\_\_ of skin that doesn't heal), doesn't displace surrounding tissue but ___ away at it * Area of _____ is common bc often the accumulation of mutations increases the likelihood that tumor cells will eventually die * Highly \_\_\_\_\_ * Invading local _____ or ____ vessels * That's why usually when tumors are biopsied the (1) is also biopsied

Answer 38

= irregular borders, ulceration, eats * necrosis * vascularized * lymphatic, blood * sentinel

Question 39

Angiogenesis = Stimulated by chronic low lvl _____ to tissue bed -\> angiogenic factors such as **(1)** stimulate nearby blood vessels to sprout new branches, serve as routes of transport of _____ into the tumor

Answer 39

Tumor creating its own blood vessels ischemia, **FGF** fibroblast growth factor, nutrients

Question 40

Carcinoma = Sarcoma = Lymphoma and Leukemia =

Answer 40

**Any cancer that arises from epithelial cells** **Cancer of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels)** pretty rare bc not usually mitotically active tissue beds **Malignant tumors derived from blood and bone marrow cells**

Question 41

Mesothelioma = Glioma Astrocytoma =

Answer 41

**Tumors derived from the mesothelial cells lining the peritoneum and pleura** (from serous membranes) ## Footnote **Tumors derived from brain cells (glial cells and astrocytes)**

Question 42

Germ Cell Tumors = Melanoma = Adenocarcinoma =

Answer 42

**Tumors derived from germ cells, normally found in the testicle and ovary** (from cells that turn into sperm and ova)​ **Malignant tumor of melanocytes** (pigment forming cells) **Form of carcinoma that originates in glandular tissue** (mucus forming cells often exocrine glands, most colon cancers are adenocarcinomas, most breast cancers are adenocarcinomas from mammary glands)

Question 43

Common Proto-Oncogenes Chart

Answer 43

Question 44

Common Tumor-Suppressor Genes Chart ## Footnote `

Answer 44

Question 45

Skin Cancer ## Footnote Most common types (2) Both almost always grow by _____ invasion and _____ metastasize Sometimes the skin cancer is malignant ______ (derived from melanocytes) Melanomas are far more _____ and often _____ to lymphatics and blood stream

Answer 45

Squamous cell carcinoma, Basal cell carcinoma local, rarely metastasize melanoma more aggressive, often metastasize

Question 46

Skin Cancer Melanomas ## Footnote * **A =** * **B =** * **C =** * **D =**

Answer 46

* **Asymmetry** - when half of the mole does not match the other half * **Border -** when the border (edges) of the mole are ragged or irregular * **Color** - varies throughout * **Diameter -** if the mole's diameter is larger than a pencil eraser

Question 47

Lung Cancer ## Footnote Nearly all cancers arise from cells in the \_\_\_\_\_ Histologically - most lung cancers are _____ cell carcinomas, \_\_\_\_\_\_\_, and undifferentiated carcinomas of both ____ and ____ cell type These cell types have characteristic patterns of spatial distribution: * Squamous and small cell undifferentiated - most frequently arise centrally near the \_\_\_\_\_\_ * Adenocarcinomas are usually ______ tumors All of these cell types behave as ______ tumors Since the lungs are rich in lymphatic and vascular supply - there are frequent lymphatic and hematological \_\_\_\_\_\_

Answer 47

bronchi squamous, adenocarcinomas, small, large * mediastinum * peripheral aggressive metastasis

Question 48

Colon Cancer ## Footnote * Histologically - tend to be mostly \_\_\_\_\_\_\_\_ * Arise mostly in (2) parts of the colon * Some are colorectal ______ arising from bowel mucosa * Often seen spread to _____ and \_\_\_\_\_\_ * If cancer gains access to portal circulation will often see _____ involvement * Other common secondary sites include ______ metastases

Answer 48

* adenocarcinomas * distal colon and rectum * carcinomas * lymphatics and vasculature * liver * pulmonary

Question 49

Breast Cancer ## Footnote * Usually an ______ of the ducts of the ______ glands * This cancer is often _______ sensitive * Occurs more often in the _______ period (ie after pregnancy and breastfeeding) and appears to be related to prolonged ______ stimulus * Metastasis to the mammary ______ occurs often but likelihood depends on size and position of the tumor within the breast * ______ metastasis occurs frequently due to lymphatic spread * (1): LN closest to cancer in this case is the _____ node

Answer 49

* adenocarcinoma, mammary * hormonally * perimenopausal, estrogenic * lymphatics * Distant * Sentinel: axillary

Question 50

Cervical Cancer ## Footnote * Typically affects _______ women (approaching \_\_\_\_\_) * 95% is _____ carcinoma * Usually grows via _____ extension and invasion * With advanced disease can get direct invasion of the _____ and more unusually the \_\_\_\_\_ * Often spreads to regional \_\_\_\_\_ * Distant metastases are unusual but when they occur they usually involve the ____ or \_\_\_\_\_

Answer 50

* perimenopausal - approaching menopause * squamous * local * bladder, rectum * lymphatics * lung or liver

Question 51

Endometrial Cancer ## Footnote * Occurs only in \_\_\_\_menopausal patients * 90% are \_\_\_\_\_\_\_\_\_ * Mostly grow centripetally _____ the uterine cavity and usually stay _____ to the uterus * May sometimes grow through the uterine lining to the _______ and underlying lymphatics and vasculature * Distant metastases are _____ but can occur

Answer 51

* postmenopausal * adenocarcinomas * toward, confined * myometrium * rare

Question 52

Prostate Cancer ## Footnote * Are almost all \_\_\_\_\_\_\_\_ * Initially tumor spreads by _____ invasion - it eventually penetrates the prostatic capsule and invades the (1) * It also commonly spreads to (1) in the pelvic region if tumor is close enough * And can also commonly spread to the (1) if close enough to the vessels in that region

Answer 52

* adenocarcinomas * local, seminal vesicles * lymph nodes * vasculature

Question 53

Ovarian Carcinoma ## Footnote * Usually affects women between the ages of \_\_-\_\_ * The carcinomas normally arise from the _____ cells that make up the _____ of the ovary - many subtypes * Has a unique mode of spread - grows via local invasion but also ____ metastases into the ______ cavity * These cancer cells tend to then preferentially invade portions of the \_\_\_\_\_\_

Answer 53

* 40-60 * epithelial, surface * shed, peritoneal * diaphragm

Question 54

Liposarcoma = It is a lipogenic tumor of large deep-seated connecive tissue spaces. \_\_\_\_\_\_\_ are common, especailly in poorly differentiated liposarcomas. (2) most common sites.

Answer 54

Malignancy of fat cells Metastases common - lungs and liver

Question 55

Primary Brain Tumors ## Footnote A unique form of tumors * None of the various types arise from neuronal cells bc they are? * They usually arise from supportive cells like (2) * Most tumors are \_\_\_\_\_\_\_ * Brain tumors grow almost entirely by _____ invasion * LN metastases? Distant mets?

Answer 55

* non-dividing, non-proliferating * astrocytes (astrocytomas), glial cell (gliomas) * astrocytomas * local * no, very rare