Disease and Human Body Exam 3

The metastatic process

"New place" one of terminal cancer stages, cancer cells enter blood stream or lymphatic system and travel to a new location in body where they begin to divide and lay foundation for secondary tumors, not all can metastasize, in order to spread cells must have ability to penetrate the normal barriers of the body so they cam both enter and exit blood or lymph vessels (picture in lecture 2)

What is epigenetics

-"Epi" genetic modifications do not change the DNA sequence which is virtually identical in all 200 cells in a persons body rather they regulate how DNA is expressed -Epigenetics control how the DNA is used, switching particular genes on or off to determine cell type and function -Post translational modifications on histone proteins orchestrate chromatin opening for gene transcription or closing for gene silencing -Epigenetics refers to stable gene expression patterns mediated by DNA methylation and or chromatin remodeling and intimately involved in cellular identity and repression of spurious transcription including from repetitive elements -Modifications to gene expression that do not involve mutation but are inherited from cell to cell during division

Gene

-A gene is a segment of DNA that codes for an RNA or protein -DNA Gene mRNA ncRNA Protein Function Function -ncRNA: non coding RNA, come in various species, short called micro RNA and long called long non coding RNA, don't code proteins but functional in a cell

What is the association between age and cancer

-As we extend lifespan as a species, we unleash malignant growth mutations in cancer genes which accumulate w aging -Cancer is intrinsically related to age, the cancer cell seeks immortality -A quarter of all American deaths will be attributed to cancer

How are benign and malignant defined

-Benign: not invade nearby tissues spread to other areas of body, more clear boundaries between tumor and healthy tissue, often be removed surgically -Malignant: invade nearby tissues or spread to other areas of body, often have abnormal nuclei (size and shape), higher likelihood of reoccurrence, surgery, chemo, radiation

What is the most common cancer type in men and women

-Both male and female lung cancer most common -In male only prostate cancer most common -In female breast cancer most common

Oncogenes vs tumor suppressor genes

-Cancer growth: genes as both the brake and gas pedals -Mutation of gene into oncogene --> like jammed gas pedal in car, increase speed of cell division -Mutation in a TSG --> behave like defective breaks, cells continue to divide uncontrolled

Genetic

-Cancer is not inherited but genes you inherit can increase your risk -You have two copies of every gene (not XY chromosome) egg + sperm = baby cell -Inherited loss of one copy of a tumor suppressor will predispose you to cancer

Chemical carcinogens

-Carcinogen: a cancer causing substance -Known chemical carcinogens: asbestos, benzene, beryllium, cadmium, arsenic, formaldehyde, mustard gas, nickel, radon, tobacco, chromium, coal emissions, diesel exhaust, wood dust, plutonium, outdoor air pollution, diethylstilbestrol -"Probable" chemical carcinogens: anabolic steroids, cisplatin, lead compounds, insecticides, acrylamide, chloroform, glass wool fibers, progesterone, selenium compounds, acetaldehyde, vinyl fluoride, ceramic fibers, azacitidine

What are examples of solid tumors

-Carcinoma: derived from epithelial cells -Sarcoma: derived from bone and soft tissues (muscles, fat, etc.) -Brain/spinal tumor: derived commonly from gilial cells -Germ cell tumor: derived from cells give rise to sperm/eggs -Neuroendocrine tumor: derived from cells release hormones -Carcinoid tumors: type of neuroendocrine tumor

What is the smallest unit of life

-Cells -Organism structure: organism --> cell --> molecules -Normal cells: nerve, bone, muscle, blood, gland, reproductive, etc.

Central dogma

-DNA makes RNA makes protein -Change in DNA sequence of cell --> lead to change in RNA and protein sequence --> lead to change in protein function

Death rates from cancer dropped...

-Dropped by 25% from 1991 to 2014 which is driven by... -Reductions in smoking, advances in early dictation and treatment, overall death rate has declined by 1.5% annually since 2001

Epigenetic gene silencing events and tumorigenesis (picture in lec 5)

-Epigenetic changes are recognized as important drivers of cancer formation, progression and resistance to therapy, interactions w the tumor microenvironment -Epigenetic changes are present in all human cancers and are now known to cooperate w genetic alterations to drive the cancer phenotype -Biochemical modifications required for epigenetic patterns are reversible -Development of the field of epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect

Lifetime probability for men and women to develop these cancer types

-Female breast cancer is 1 in 8 -Male prostate cancer is 1 in 9 -Lung cancer in female is 1 in 17 -Lung cancer in male is 1 in 15

Why will cancer surpass heart disease as number one cause of death in US

-First ask why heart disease is decreasing -People understand the biology of heart disease better than cancer cells as well as ways to prevent heart disease, treatments, etc.

What happens at each stage

-G1 phase: accumulation of signal to pass R point -S phase: all DNA replicated -G2 phase: prepare for mitosis -M phase: cell divides into 2 daughter cells (chromosome condensation) -G0 phase: non dividing quiescent state (differentiated)

Causes of cancer

-Genetic, epigenetic, environmental, sporadic -Cancer is ultimately a disease of gene expression in which complex networks governing homeostasis in multicellular organisms become deranged, allowing cells to grow w out reference to needs of organism as a whole

Treatments

-Gleevec (imatinib) targets BCR ABL protein -Healthy cells do not have BCR ABL so drug can only target cancer cells -One of the very few actual cures for cancer -Ph+ CML patients who are in remission after 2 years of imatinib treatment have the same life expectancy as someone who does not have cancer

Pros for testing for cancer susceptibility genes

-In some cases you can take drugs to reduce your risk, it can scare you into making lifestyle choices that reduce risk, sometimes surgery can reduce risk -BRCA mutation, have mastectomy/oophorectomy preventative treatment w tamoxifen (mary claire king) -APC mutation, patients can have colectomy

Cancer susceptibility syndromes (familial)

-Li Fraumeni Syndrome: loss of one copy of p53, 500 fams diagnosed worldwide, risk of developing cancer is 50% by age 30, female lifetime risk is 100%, male lifetime risk 73% -Familial adenomatous polyposis: mutation of one copy of APC (TSG), 1 in 10,000 people, causes many pre cancerous colon polyps, risk of colon cancer 87% by age 45 -BRCA mutations: inherited susceptibility to breast and ovarian cancer, BRCA1 and 2, 12% of normal women develop breast cancer 1.3% ovarian cancer, 60% of BRCA1 carriers develop breast cancer 30% ovarian cancer, 45% of BRCA2 carrier develop breast cancer 15% ovarian cancer -BRCA mutations also relevant to men, increases risk for male breast cancer and prostate cancer although not as dramatic as women's -BRCA mutations inhibit DNA damage repair (central player, other paths can lead to cell death or arrest)

What are 4 main building blocks of cell and name of their polymers

-Lipids = fatty acids -Proteins = amino acids -RNA/DNA = nucleic acids -Polysaccharides = carbohydrates -Monomers --> polymerization --> polymer

What are examples of liquid tumors and why are they called this

-Liquid = originate from blood cells -Leukemias: derived from blood forming tissues of bone marrow -Lymphomas: derived from T or B lymphocytes (Hodgkin and nonHodgkin) -Myelomas: derived from plasma cells (differentiated B cells) (priority issue for precision health research, area research impacts Indiana Health)

Chemical induced mutations

-Many chemicals can interact w the DNA directly and damage the DNA -Many chemicals can promote responses in cells that increase levels of DNA damaging agents in cells -In either case it leads to DNA damage that can lead to sequence changes (mutations)

What are cyclins

-Most important core cell cycle regulators, a group of related proteins and there are 4 basic types found in humans -Each associated w particular phase, transition, or set of phases in cell cycle and helps drive events of phase or period -Levels of different cyclins vary across cell cycle -Typical when present at low levels for most cell cycle but increases strongly at stage needed

What do mutations do to a cell

-Mutations very common, they can do nothing (most common), kill the cell (rare, second most common), make cell grow (extreme rare) -Only mutations we'll notice EVER are those that make cells divide -Mutations can be inherited or acquired, inherited= is present in egg or sperm that formed child, acquired (somatic)= not come from parent but sometime later -Acquired mutations more common than inherited, most cancer caused by acquired

Radon (pictures in lec 6)

-Naturally occurring radioactive gas -Responsible for 21,000 lung cancer deaths per year -58 deaths per day

Function of organelles

-Nucleus: houses DNA (genetic info of cell; same in every cell) -Mitochondria: "powerhouse" of cell - produces energy for cell function -Cytoplasm: Fluid filled, jelly like portion of cell - houses other organelles (ribosome, golgi, ER...) -Plasma membrane: semi permeable, bilipid membrane; separates inside from outside of cell, composed lipids, proteins, and carbohydrates (communication w environment)

Cancers caused by mutations in 2 types of genes

-Oncogenes: genes that promote cancer, mutations activate these genes -Tumor suppressor genes: genes that inhibit cancer, mutations inactivate these genes

Oncogenes

-Otherwise normal gene expressed at too high level -Otherwise normal gene expressed in wrong cell/wrong time -Mutation creates abnormal protein that is "stuck on" -Examples: proto oncogenes -MYC normal gene, when over expressed can drive tumor suppressor genes -ERG expressed during wrong time, drive cells to migrate (regulatory sequence) -RAS impacts function of protein (most common mutated)

Examples

-Pediatric compared to adult cancers -Differences in number of mutations in the same type of cancer

Gene fusions

-Philadelphia chromosome BCR-ABL an abnormality of chromosome 22 in which part of chromosome 9 is transferred to it. -Bone marrow cells that contain Philadelphia chromosome are often found in chronic myelogenous leukemia and sometimes found in acute lymphocytic leukemia -A piece of chromosome 9 and piece of chromosome 22 break off and trade places, BCR ABL gene is formed on chromosome 22 where the piece of chromosome 9 attaches, the changed chromosome 22 is called Philadelphia chromosome -Ph chromosome BCR ABL fusion is detected in 90% of patients w chronic myelogenous leukemia (CML) -Can also be present in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) but lower frequencies

Cons for testing for cancer susceptibility genes

-Preventive treatments can decrease quality of life, can increase stress and decrease quality of life especially if there is no preventative measure, can be expensive, could face discrimination by insurance companies -Usually testing is reserved for relatives of people known to have these mutations

What is cell differentiation

-Process in which a cell changes from one cell type to another, cells become more specialized, less than 200 cell types known in humans, terminally differentiated have reduced proliferation -Adult tissue, normal stem cells, brain, bone marrow, breast

Who decides what compounds are carcinogenic

-Scientist, various agencies such as IARC, NTP, EPA -IARC: 1, 2A, 2B, 3, 4 -NTP: known and reasonable -EPA: A, B, C, D, E

What is a simple definition of cancer

-Simple: all share a fundamental feature, abnormal growth of cells -Cancer is a disease caused bu uncontrolled growth of a single cell -Growth unleashed by mutations, changes in DNA specifically affect genes that initiate unlimited cell growth -A cell that can't stop growing; cell growth w out barriers: to grow, adapt, recover, repair - to live at cost of our living -Cancer cells are a more perfect version of ourselves

What are primary types of tumors and subcategories

-Solid and liquid tumors -Solid = oncologist -Liquid = hematologist -Subcategories are different types of solid and liquid tumors

Five year survival rates for lung cancer/stage of distribution for lung cancer (pictures in lec 6)

-Tobacco smoke causes 80-90% of lung cancers -Smoking cessation is most important way to stop lung cancer

Tumor suppressors

-p53 -Genes that guard against cancer -Mutation inactivates protein -Mutation turns off gene expression -Loss of heterozygosity (LOH) (loss of self control/growth)

Epigenetics consist of

1. DNA methylation 2. Histone modifications 3. Small and non coding RNAs 4. Chromatin architecture, nucleosome occupancy -Chromatin structural changes in cancer cells, abnormal DNA methylation in tumor progression (pictures in lecture 5)

Steps of cancer cells spreading thru body

1. Growing into to invading nearby tissue 2. Moving thru walls of nearby lymph nodes or blood vessels 3. Travel thru lymphatic system and bloodstream ti other parts of body 4. Stopping in small blood vessels at a distant location invading the blood vessel walls and moving into surrounding tissue 5. Growing in this tissue until a tiny tumor forms 6. Causing new blood vessels to grow which creates a blood supply that allows tumor to continue growing

What are environmental causes of cancer

1. Things that cause DNA damage 2. Things that cause inflammation 3. Obesity 4. Alc 5. Viruses

Tumor suppressor genes can become inactivated by 3 pathways

1. Thru mutations in which their functions become disabled 2. A gene can be completely lost and thus not be available to work appropriately (loss of heterozygosity) 3. A gene can be switched off in a somatically heritable fashion by epigenetic changes, rather than by mutation of DNA sequence

Tissue stem cells and normal tissue renewal

4. Falling leaves: apoptosis 3. Leaves: very many differentiated tissue cells 2. Branches: progenitor cells 1. Trunk: few stem cells

Types of cancer

> 100 types, named for organs or tissues where cancers come from, described by the type of cell that they resemble, such as an epithelial cell or squamous cell

What is cell migration

Ability of cells to move around, early stages usually benign and remain confined, as grow become malignant begin to break boundaries and invade other tissue, invasive cancer secrete proteases that enable them to degrade extracellular matrix at tissues boundary, proteases also give cancer cells ability to create new passageways in tissues, break down junction that join cells together gaining alleles to new territories

Which can protect daughter cell from getting damaged DNA

Apoptosis, R point, p53, G1/S checkpoint

Testing and patents

BRCA1 discovered in 1994, Myriad genetics, 500 million in annual revenue in 2012, patent invalidated by supreme court in 2013

What are 2 main types of tumor "aggressiveness"

Benign (non cancerous) and malignant (cancerous)

Influences on uncontrolled cell division

Cancer cells may make own growth factors, have growth factor pathway that are stuck in "old" position, thick neighbor cells into producing factors to sustain

Differences between cancer and normal cells

Cancer cells: cells gone wrong, no longer respond to many signals that control cellular growth and death, cancer cells less specialized than normal, normal cells mature into very distinct cell types w specific functions and caner cells don't, cancer cells divide more rapidly than progenitors and become less dependent on signals from other cells.

What area of cancer biology is most closely associated w new cancer cases

Cancer formation or "carcinogenesis"

What is unique about cell cycle in cancer

Cancer has uncontrolled progression thru cell cycle, ignore the R and go thru different phase faster than normal cell

Premise

Cancer is a genetic disease, cancer is caused by a mutation

Conclusion

Cancer is unchecked cell growth, mutations in genes can cause cancer by accelerating cell division rates or inhibiting normal controls on the system such as cell cycle arrest or programmed cell death, as a mass of cancer cells grow it can become tumor, cancer cells can invade neighbor tissue, cancer cells may break off and travel to other parts of body leading to formation of new tumors at sites

What area of cancer biology is most closely associated w cancer death

Cancer progression and metastasis

Factors that have an impact on 5 year survival rates in cancer

Cancer type, if diagnosed in distant stage

Most common type of cancer

Carcinomas include most common and deadly cancers

What is a cell cycle checkpoint

Control mechanisms to ensure proper progression of cells

Why is cell migration important in cancer biology

Critical for cancer metastasis, invasive tumor cells travel thru the strona just prior to their intravastation towards hematogenous spread

Should there be routine BRCA mutation screening

Currently not covered by insurance, preventive mastectomy/oophorectomy not covered by insurance, 23andme genetic testing only tests 20-30 out of 1800 possible mutations in BRCA genes

G1 checkpoint and DNA damage

DNA damage can and will happen in many cells of body during a persons lifetime (sun UV rays). Cells must deal w damage, fixing it if possible and preventing cell division

What does grading assess about a patient's tumor

Description of tumor based on how abnormal the tumor cells and tissue look histology, typically assessed by a pathologist after a biopsy, grading is tumor type specific, general guidelines GX can't be assessed or G1-4, higher number = worse tumor

Why has Alzheimer's made its way to top 10 causes of death

Disease of aging and same association between aging and Alzheimer's is seen w aging and cancer

Carcinoma cell

Dissemination occurs via 2 mechanisms, single cell dissemination and collective dissemination of tumor clusters

Why is p53 important

Ensuring cells don't divide when their DNA is damaged, p53 prevents mutations from being passed to daughter cells, when defective or missing mutations can accumulate quickly, potentially leading to cancer, out of all the entire human genome, p53 is the single gene most often mutated in cancers

Gene ampflications

Epidermal growth factor receptor (EGFR) gene amplification in cancer (picture in lec 5)

What type of cell do carcinomas arise from

Epithelial cells: any cell lining an exterior surface

How cancer arises (picture in lecture 3)

Examples: smoking related cancers have much higher numbers because carcinogens in smoking lead to more mutations, etc. Sun related cancers have higher numbers because sun rays which results in DNA change, etc.

Cyclin expression cycle

G1 cyclins are unusual in that they are needed for much of the cell (picture in lecture 2)

What are the 5 main stages of the cell cycle

G1 phase, S phase, G2 phase, M phase, G0 phase

Top 5 causes of death in the US

Heart disease, cancer, unintentional injuries, chronic lower respiratory disease, and stroke/cerebrovascular disease

What does Gleason score indicate

High score indicates worse tumor, more likely cancer will grow and spread more quickly

Importance of the G1 checkpoint

How DNA damage halts cell cycle in G1

Why is cell differentiation important in cancer biology

In cancer more differentiated tumor cells, more benign the tumor, differentiated tumor cells can go backwards or de-differentiate to a more primitive or stem like cell state and become "cancer stem cells"

Lifetime probability of developing any cancer

In women and men to develop all sites is 1 in 3

Consequences of changes in activity of inhibitors and activators of cell cycle

Inhibitors keep cells from dividing, little activity of these can promote cancer, positive regulators of cell division lead to cancer if too active, changes in activity due to mutations in genes that encode cell cycle regulator period

What is p53

Key to damage response is this protein known as guardian of genome, works on multiple levels to ensure cells don't pass on their damaged DNA thru cell division

Of following stages of distribution of female breast cancer in US which most common

Localized

Localized, in situ, regional, and distant

Localized: no sign spread, in situ: not spread from where 1st formed, regional: spread to nearby, distant: spread to far other areas

What does staging assess about a persons tumor and what are the 4 main stages of staging

Location of primary (original) tumor, tumor size and extent of tumors, lymph node involvement (whether or not cancer spread nearby lymph nodes), presence or absence of distant metastis (whether or not cancer spread to distant areas of body)

What are good sources for finding more about results from cancer research/clinical trials

NIH reporter, pubmed, clinical trials, american cancer society (ACS), and other cancer foundations

What government organization is tasked w studying and disseminating info ab cancer

National Cancer Institute (NCI)

Which agency funds vast majority of cancer research in US

National Institutes of Health (NIH)

Is cancer a single disease

No, many diseases

Cellular composition

Often modeled as a hierarchical scheme w stem cells at the top of hierarchy

What cancer is usually diagnosed at a late stage

Ovarian cancer, pancreatic cancer, etc.

What is pluripotency

Potential to become any cell type and is potential observed in stem or progenitor cells at the beginning of the cell differentiation process slowly lost as the cell differentiates and gains specialized functions

R point definition and characteristics

Restriction point before cell commits to S phase (G1/S checkpoint), main decision point for a cell to chose whether or not to divide, passing R point is result of accumulation of cellular growth signals

What is the seed and soil hypothesis in cancer metastasis

Stephen Paget 1889, as seed required right soil to grow so do cancer cells require right environment to survive, different cancer cells have different preference ab which organs/locations in body, breast cancer cells spreading to bone

Which is example of cancer prognosis

The 5 year survival for pancreatic cancer is 8.5%

Traveling metastatic cancer cells face challenges when trying to grow into new areas...

The blood stream represents a hostile environment for circulation tumor cells: exposed to rapid clearance by natural killer cells, fragmentation due to by natural killer cells, fragmentation due to physical stresses encountered in transit thru circulation

Environmental causes of DNA damage

Tobacco smoke, radon, UV light

Which decreases likelihood of passing R point in cell cycle

Tumor suppressor genes

Cancer is a disease caused by

Uncontrolled growth of a single cell

What is cell apoptosis

Unfixable DNA damage, normal cell will die thru program cell death

Gleason scoring system

Used to help evaluate prognosis of men w prostate cancer using samples from a prostate biopsy

Protein

What do they do: everything, gene expression, DNA replication, cell division, signaling (intracellular) (cell to cell), metabolism

What is cancer prognosis

What the expected outcome is when diagnosed, often give certain amount of time, often given percentage of people who live for 5 years

What makes one cell different from another

Which genes they express (picture in lecture 3)