Lecture 12 - Cancer

Question 1

Totipotent cell

Answer 1

Fertilized Ova capable of becoming ANY cell in the human body

Question 2

Multipotent cell

Answer 2

has eliminated many types of cells by permanently turning off the associated genes ex) endoderm, ectoderm, mesoderm

Question 3

Pluripotent Cells

Answer 3

narrowed down possibilities to a few related cells

Question 4

Unipotent Cells

Answer 4

can only turn into one type of cell, but it is still a stem cell (it retains the properties of a stem cell)

Question 5

Mature Differentiated Cell

Answer 5

functional tissue cell, unresponsive to growth factors

Question 6

Be prepared to discuss the process of reverse differentiation in cancerous cells in terms of totipotent, etc.

Answer 6

*Each time a cells divides it has the option to irreversibly differentiate or to remain a stem cell. The cell should normally permanently turn off genes and express only those genes that pertain to the mature specialized cell. This involves stimulation of growth factors, maturation factors, and neighboring cells through cell-cell signal proteins.

CANCER CELLS CAN REVERSE DIFFERENTIATE BY TURNING ON GENES THAT SHOULD BE TURNED OFF. Now the cancer cell is not differentiated and can keep dividing. It can express any gene of any cell in the body…scary!

Question 7

Tumor

Answer 7

abnormal growth due to uncontrolled cell proliferation that serves no function

Question 8

Neoplasm

Answer 8

new growth

Question 9

Benign Tumor

Answer 9

not referred to as cancers, growths that are encapsulated and well differentiated, cell retain normal tissue function

Question 10

Cancer

Answer 10

now reserved for malignant neoplasms, characterized by rapid growth, loss of differentiation, and a lack of normal tissue organization

Question 11

Carcinoma

Answer 11

epithelial tissue

Question 12

Adenocarcinoma

Answer 12

glandular epithelial tissue

Question 13

Sarcomas

Answer 13

connective tissue

Question 14

Leukemias

Answer 14

blood forming organs

Question 15

Gliomas

Answer 15

glial cells of the CNS

Question 16

Lymphoma

Answer 16

lymphatic tissue

Question 17

Note

Answer 17

Just so you know, rules of nomenclature are - 1. named after tissue of origin, 2. benign or malignant (invasiveness,grade), 3. degree of differentiation (grade)

Question 18

Describe each of the division of cancer staging.

Answer 18

Grading:
Grade I - closely resembles tissues of origin, retains some specialized function, has not invaded the capsule (benign neoplasm)

Grade II - less resemblance, more variation in size and shape, increased mitosis, has begun to invade the capsule (malignant neoplasm)

Grade III - does not closely resemble the tissue of origin, much variation in size and shape, greatly increased mitosis (poorly differentiated malignant neoplasm)

Grade IV - no resemblance to tissue of origin, great variation of size and shape of tumor cells (anaplastic mestastatic neoplasm)

Question 19

Describe each of the division of cancer staging.

Answer 19

Stage I - cancer is confined to organ of origin

• what we would call a carcinoma in situ - refers to a tumor that is still in tissue of origin and has not yet invaded or borken though basement membrane beneath or capsule

Stage II - cancer is locally invasive, broken through capsule

Stage III - cancer has spread to regional structures ex) local lymph nodes

Stage IV - cancer has spread to distant organs

Question 20

Define and differentiate between cancer GRADING and cancer STAGING.

Answer 20

Cancer Grading = it estimates the degree of differentiation or lack thereof of the cancer cells

(Differentiation)

Cancer Staging = rating of the cancers invasiveness

(Invasiveness)

Question 21

Be prepared to distinguish normal roles of the following genes and the roles they play in transformation of normal cells into cancer cells.

Tumor suppressor Gene V. Proto-oncogene

Answer 21

Tumor suppressor gene: genes which inhibit cell growth and division and promotes terminal maturation

one can be inactivated by a point mutation (both could be hit by a point mutation over time) OR a single active gene will be turned off by epigenetic regulation (silencing of a gene by de-acetylation of histone or methylation of the genes DNA) thus only requiring one point mutation, ACTS LIKE A RECESSIVE GENE

Proto-Oncogene: growth related gene (codes for proteins that control growth and differentiation)

point mutation, ACTS LIKE A DOMINANT GENE, found in many cancers especially colorectal and pancreatic cancer

Question 22

Be prepared to distinguish normal roles of the following genes and the roles they play in transformation of normal cells into cancer cells.

Caretaker genes V. Proto-oncogene

Answer 22

Caretaker Gene: “guardians of the genome” - genes that repair damaged DNA or DNA replication mistakes. When this are dysfunction, the number of mutations increases dramatically

Proto-oncogene: growth related gene, codes for proteins that control growth and differentiation

point mutation, ACTS LIKE A DOMINANT GENE, found in many cancers especially colorectal cancer and pancreatic cancer

Question 23

Be prepared to distinguish normal roles of the following genes and the roles they play in transformation of normal cells into cancer cells.

Insertion of a viral DNA into normal human genomes

Answer 23

Tumor virus - inserts its DNA into the host cells and causes uncontrolled cell growth and division

Question 24

List the systems or mutations or silencing that must occur for metastic cancer cells to happen. Be prepared to discuss why leukemia cancers don’t need as many mutations.

Answer 24

Carcinogenesis: Formation of a tumor is not a one hit event, many factors are believed for transformation to occur. It is an evolutionary process.

*** leukemia doesn’t need as many mutations because it is not as age dependent

The steps:

a) 1 mutation in an oncgene (responds abnormally to Growth Factors). Can be GF, or receptor, or signal cascade to nucleus (RAS mutation signals cell to grow in absence of GF)
b) 2 mutations in tumor suppressor gene (either 2 point mutations or one point mutation and epigenetic silencing) - decreases responsiveness to mitosis inhibiting and cell differentiation factors
c) mutation in genes regulating glycosphingolipids - increased responsiveness to GF
d) mutation disabling the apoptosis process, usually TP53 gene (prevents protective cell suicide)
e) mutation or alteration in genes expressing telomerase (immortal growth)
f) mutation in genes involved with the expression of fibronectin (Cell adhesion) - used to anchor the cell to neighboring cells or surrounding CT
g) mutation of genes making or regulating gap junctions, loss of contact inhibition
h) abnormal secretion of angiogenic growth factors

Question 25

List the components that are involved with cell-to-cell contact inhibition and communication.

Answer 25

1. Gap Junctions | 2. Glycoproteins and glycolipids

Question 26

List the components that are involved with cell-to-cell adhesion

Answer 26

1. Fibronectin - this forms cadherins and integrins 2. Anchorage Proteins - desmosomes, adherins, junctions * normal cells need to be anchored to undergo mitosis, cancer cells undergo anchorage independent mitosis * protease activates plasminogen which disrupts extracellular matrix and decreases adhesiveness; allows cancer cells to escape the capsule

Question 27

List the components that are involved with cell apoptosis

Answer 27

1. P53 gene

Question 28

List the components that are involved with control of cell division.

Answer 28

1. Tumor supressor Gene 2. Proto-oncogene 3. Glycosphingolipids 4. Gap Junctions - contact inhibition

Question 29

List the components that are involved with limitation of cell division and protects chromosome ends during mitosis

Answer 29

1. Telomerase 2. Tumor supressor genes 3. Glycosphingolipids 4. Proto-oncogene 5. Gap Junctions

Question 30

Define and list the types of tumor cell markers. Be prepared to describe three ways they are used in a clinical setting.

Answer 30

Tumor cell markers: substances secreted by the cancer, on the tumor cell membranes or released into the ECF compartments They are useful in: 1. identifying persons at high risk for cancer, 2. diagnose the type of cancer, 3. follow the clinical course of the cancer, effectiveness of treatment Types of markers: 1. Hormones - ectopic hormones produced by tumor cells of a non-endocrine origin ex) ACTH, Catecholamines OR immature fetal forms of a hormone ex) hCG, AFP 2. Enzymes - immature or fetal types of an enzyme or in abnormal proportions 3. Genes - oncgenes, mutated forms - phosphokinases turn on and off pathways - DNA binding proteins - Cell growth factors 4. Antigens - production of neoantigens (non self, assist the immune response to destroy the tumor) OR normal antigens: PSA (prostate specific antigen), more cells increase the likelihood of CA 5. Antibodies - ineffectual immunoglobulins ex) M proteins in multiple myeloma 6. Proteins - AFP (alpha fetal protein), secreted by liver cancer cells and germ line cancers

Question 31

Be prepared to discuss the role of inheritance in the development of cancer. Differentiate the role of inherited mutation v. spontaneous mutations and the affect an inherited mutation may have on the average age of CA onset.

Answer 31

Inherited CA: mutations must occur in GERM LINE CELLS (not passed on to the next generation of the mutation is in somatic cells) Inherited mutation v. Spontaneous mutation: Inherited mutation is in the germ line cells where as spontaneous mutation would be the mutations that lead to cancer during the life time of the individual within the somatic tissues. An inherited mutation will increase the persons susceptibility to cancer at a younger age. Whereas spontaneous mutations may be prevented and potentially reversible.

Question 32

Explain the role of growth factors and hormones in driving the abnormal growth rate of tumor cells. List 4 mechanisms mentioned in lecture that exaggerates cell growth and mitosis.

Answer 32

The proto-oncogene and oncgene are growth related genes that when they are mutated cause uncontrolled growth. Overstimulation of these genes will lead the cells to become cancerous. What 4 things cause exaggerated cell growth and mitosis? 1. cancers autocrine secretion of their own growth factors 2. reduction in the amount of growth factor necessary (receptor up-regulation) 3. defects in the growth factor receptor, hyper stimulation (active w/o GF) 4. alteration in receptor signal pathway (2nd messenger system) = hyper stimulation

Question 33

List 6 types of oncotic viruses and be familiar with the types of tumors and cancer they are associated with. Suggest mechanisms by which viruses may affect the cell cycle in carcinogenesis.

Answer 33

Papillomavirus: vaginal warts and virtually all cervical CA Hepatitis B and C virus: liver adenomas Adenovirus Epstein Barr Virus: B cell Lymphoma Herpes Viruses HIV Human T cell Leukemia Lymphoma Virus Mechanisms of Viruses: a) direct mutagenesis of proto-oncgenes b) insertion mutagenesis at specific sites - their own oncogenes V onc leads to the activation of v-onc or the cells own c onc genes c) indirect - cause rapid cell proliferation, which are more subject to spontaneous mutation * cervical and liver cancers account of 80% of viral linked cancers!

Question 34

List the complications of both cancer and the treatments of cancer. Describe briefly the mechanism for these complications.

Answer 34

1. Para- neoplastic syndromes: some tumors release hormones acting as ectopic sources. They don't respond to negative feedback controls = hypersecretion syndromes ex) serotonins, flushing, diarrhea, and wheezing 2. Pain - cause could be pressure, bowel or blood flow obstruction (ischemia), stretching of the viscera (abdominal), tissue destruction (bone), inflammation and kinin and cytokine release 3. Fatigue - causes could be sleep disturbances, biochemical changes, nutritional status, mm. loss, anemia 4. Cachexia - wasting away of lean body mass, may have to do w/ stress response. Increase sympathetic stimulation and cortisol. Causes: anorexia, poor use of glucose, decrease insulin secretion, increased catabolism of proteins, decreased peristalsis, increased triglyceride hydrolysis, aversion to red meat 5. Anemia: causes are chronic bleeding, chemotherapy and other medical therapies, malignancy in hemopoietic tissues, malnutrition 6. Leukopenia and Thrombocytopenia: chemotherapy and malignancy in hemopoietic tissues 7. Infection: reduction of immune system components, loss of gut barrier (invasion by normal flora) --> GI tumor or chemotherapy 8. GI complications: loss of gut barrier due to decreased cell replacement (chemo), loss of absorption surface area, diarrhea, sepsis from loss of gut barrier 9. Alopecia (hair loss), usually temporary

Question 35

List the steps to metastasis and describe mutations or transformations needed for cancer cells to break away from the parent tumor, survive transport, and enable them to establish metastastic colonies away form the original tumor site. Explain why some CA cells metastasize to different organs. Part one - The Steps * most common site of metastasis is through lymph, CA cells found in lymph nodes are usually first clinical evidence that metastasis has occurred, lymph nodes can act as a barrier to metastasis for a period of time until secondray local invasion causes another release from the lymph nodes

Answer 35

1. Local Invasion: a) cellular multiplication b) release of lytic enzymes (hydrolases, protease, plasminogen activators, type IV collagenase - digest the extracellular matrix and basement membranes to which normal cells anchor themselves) c) mechanical pressure - finger like projections in areas of least resistance, compresses local cells and blood vessels causing mechanical damage and hypoxia d) decrease cell-cell adhesion - loss of fibronectin which regulates cell attachment or defective fibronectin e) increased motility - increased sensitivity to motility factors thought to be autocrine secretion by tumor cells themselves or inflammatory cytokines 2. Penetration into blood vessels or lymphatic or both - tumor cells attachment: tumor cells have laminin receptors which enable them to attach to basement membranes --> actively invade the capillary wall - release proteolytic enzymes that allow them to degrade the basement membrane and extracellular matrix and creates room for CA cells to move in 3. Release into lymph or blood 4. Transport to a secondary site by blood or lymph or both -- extend pseudopodia into the tissue and pull themselves into the tissue and out of the blood vessel 5. Arrest, adhere, and proliferate at the secondary site 6. Neovascularization - secrete VEGF and PDGF to stimulate new vessel growth to deliver nutrients to sustain tumor - angiogenesis: normal cells prevent the development of blood vessels by secreting thrombospondin, tumor cells can't secrete thrombospondin - TAMS: macrophages that produce anti-inflammatory mediators and induce cell proliferation, angiogenesis, and woundhealing; they block Tc and NK cell function, prevent the immune response

Question 36

List the steps to metastasis and describe mutations or transformations needed for cancer cells to break away from the parent tumor, survive transport, and enable them to establish metastastic colonies away form the original tumor site. Explain why some CA cells metastasize to different organs. The mutations

Answer 36

Mutations needed for cancer cells to break away from parent tumor: 1. Loss of fibronectin - loss of adhesiveness 2. Secrete protease - disrupts extracellular matrix and decreases adhesiveness (allows cancer to escape the capsule) 3. decreased anchorage proteins - desmosomes, adherens, junctions are all needed for normal cells to anchor to undergo mitosis (CA cells don't need to be anchored to undergo mitosis) * the success of cancer cells is greater if clusters of malignant cells release and adhere together or they cluster with platelets

Question 37

Explain why some CA cells metastasize to different organs.

Answer 37

a) loss of cell adhesion and migration lead to the movement of cancer cells into circulation and/or lymph vessels B) they go to first capillary bed encoutered c) organ trophism - tumors and individual cells are attracted to certain organs or tissues, those organs either secrete chemotaxic chemical or cancer cells preferential adherence to tissue receptors of the organ

Question 38

Describe the immunological defenses the body has against tumors. Identify which cells and systems are most heavily involved and which are most effective.

Answer 38

A) If tumor cell expresses a tumor specific antigen, the immune system will reject the tumor. Targeted by Tc cells. B) Immunologically depressed individuals have greater risk of tumor development Mechanism: 1. If B lymphocytes are activated, then it usually is a tumor specific antibody (TSA) Two ways to kill cancer with a TSA: a) activate complement B) antibody dependent cell-mediated cytotoxicity (ADCC) - Fc portions bind to the membrane of monocytes, neutrophils, b cells, certain null cells called killer cells Allows cells to recognize the cancer cells 2. NK cells - first line of defense against cancer cells, activated with chromosomal changes are activated when MHC type I down regulates (innate immunity) 3. Tc cells - most effective defense for tumor rejection a) attack TSA antigens that are displayed on MHC I marker b) differentiation stimulated by presentation of the TSA by macrophages c) activated by Th

Question 39

Identify 7 specific ways in which CA cells are able to avoid immunological detection and/or annihilation.

Answer 39

1. Mask or modify their antigens 2. Secrete immuno-suppressive substances ex) interleukin, prostaglandin E 3. Blocking factor - antibodies that bind to and block the antigen but don't activate complement or bind to the ADCC system 4. Normal antigens active suppressor lymphocytes 5. Activate TAMS - phase 2 macrophages that promote healing (TAMs block NK and Tc function, prevent the immune response)

Question 40

List the 4 general treatment modalities used to combat cancer and describe generally how they work and what their limitations and advantages are.

Answer 40

1. Chemotherapy - kills cells that are active in mitosis or capable of mitosis - hopefully the chemo eradicates enough cells that the body can kill the rest - combos of different types of chemical agents have been the most successful. each drug attacks the tumor at specific weakness - some cells in the tumor mass may be resistant 2. Radiation - focuses on only the tumor and hopefully doesn't damage too severely the tissue around it, damages or destroys large macromolecules like DNA 3. Surgery: removes the whole tumor before it metastasizes; it is preventative ex) mastectomy; it removes pressure to alleviate pain, debulk prior to chemo, and determine staging 4. Immunotherapy - selectively kill tumor cells while sparing normal cells, memory cells for prevention of emergence of primary tumor ex) BCG - bacterial wall extracts (Activates NK and macrophages) some success with urogenital and lung CA DNCB - dinotrochlorobenzne, painted on skin tumor, causes hypersensitivity response (Type IV similar to poison Ivy) LAK - lymphokine activated killer cell therapy, cultured Tc cells in IL-2 activated against TSA, LAK cells resinserted into pt. cause lysis of tumor cells, used successfully against melanoma and renal cell carcinoma Monoclonal antibodies - used to diagnose and monitor treatment results, goal is to mediate tumor rejection, has been most successful against hematologic and lymphatic cancers, conjugated antibodies attach radio active isotopes or toxins when antibodies bind to tumor cells, they kill target selectively as with radioactive iodine with Thyroid CA

Question 41

Chemotherapy

Answer 41

Kills cells that are active in mitosis or capable of mitosis. Hopefully the chemo eradicates enough cells that the body can kill the rest. Combos are used b/c they are most successful

Question 42

Radiation

Answer 42

focuses only on the tumor and hopefully doesn't damage too severely the tissue around it. Damages or destroys large macromolecules like DNA

Question 43

DNCB antigen modification

Answer 43

dinitrochlorobenzene body first sensitized, then DNCb is painted on skin tumor, causes hypersensitivity reaction (Type IV, similar to poison Ivy)

Question 44

Radiation

Answer 44

focuses only on the tumor and hopefully doesn't damage too severely the tissue around it. damages or destroys large macromolecules like DNA.

Question 45

Radioimmune therapy

Answer 45

selectively kills tumor cells while sparing normal cells; memory cells for prevention of emergence of primary tumor

Question 46

LAK Tc cell culture

Answer 46

lymphokine activated killer cell therapy cultured Tc cells in IL-2 activated against TSA. LAK cells reinserted into pt. causing the lysis of tumor cells. Used successfully against melanoma and renal cell carcinoma

Question 47

BCG immuntherapy

Answer 47

bacterial cell wall extracts are injected into tumor activated NK and macrophages some success with urogenital and lung CA

Question 48

Monoclonal antibodies

Answer 48

1. used to diagnose and monitor treatment results 2. Goal: to mediate tumor rejectoin 3. Has been most successful against hematologic and lymphatic cancers 4. Conjugated antibodies: attach radioactive isotopes or toxins, when antibodies bind to tumor cells, they kill target selectively as with radioactive iodine with Thyroid CA