evol/med 6

why do animals get cancer?

Evolution of aging Stem cells Somatic mutations

cell type in cancer

Squamous - flat epithelial cells Myeloid - blood cells Lymphoid - lymphocytes or macrophages Adenomatous - ductal or glandular cells: colon, thyroid, prostate, etc

Tumors modify their microenvironment

Tumors change metabolism so that they lower pH in microenvironement -induces angiogeneis (growth of blood vessels) gives tumors more resources -lower pH will inhibit immune system response, inhibit t cell maturation -makes environment more nutrient friendly.

susceptibility to cancer: trade offs

A lot of genes that are involved in risk of cancer gives benefits in like reproduction, tissue maintenance, evolvability, development, sexuality.

How are somatic cells kept under control?

Cancer is due to cells escaping from control -Cells all agree to play happy together and on same playing field and if one decides to be rebel and escape then that is a problem. Tumor-suppressor genes -Control differentiation: inappropriate proliferation -> apoptosis -Deal with damage: if DNA damage cannot be repaired -> apoptosis p53: controls both responses -Disabled by mutation in most cancers Somatic cell -> Cancer cell: multiple mutations needed -not one stop mutational process, multiple step process.

cancer evolution: summary

Cancer starts when a combination of mutations (somatic and possible germline), produce cells that slip out of the cell cycle and cell death controls Genetically heterogeneous - compete for resources and space Competition favors clones that grow fast, disperses, and invade Short sighted and selfish

cancer phylogenetics summary

Cancers originate earlier than expected Single biopsies underestimate genetic heterogeneity Treat the tree, not just a twig or branch Can use phylogenetic analyses to evaluate cancer treatments

tissue type in cancer

Carcinoma: epithelial cells - 90% of all tumors Sarcoma: connective tissue - 2% of all tumors Leukemia: circulatory or lymphatic tissue - 8% of all tumors

cancer and the immune system

Cells evolve and will evolve to outcompete others and will be selected for ability to evade or suppress our immune system. Cancer cells are modified self Immune system has fail-safe mechanisms to not attack self Immune system attacks self cells with pathological traits Inappropriate metabolism, growth, movement Cancer evolves to avoid or suppress immune attack Disrupt immune cells, signals, and receptors -has to parallels to pathogen evolution

cancer and chemotherapy

Chemotherapy strongly selects for rapid evolution of resistant clones -Parallels with antibiotic resistance -Which ever one reproduces fastest will increase in frequency. Will kill off all the ones that are resistant. If clone A was susceptible then will be killed and B will rise in frequency.

Chemotherapy basics

Cytotoxins 5-flurouracil - blocks DNA synthesis Cisplatin - binds to DNA, causing problems in DNA replication and transcription -Have things that interfere with synthesis and replication Targeted therapies Gleevec - inhibits the oncogene BCR-Abl (leukemia) Tamoxifen - blocks the estrogen receptor that is functional in breast cancer Gefinitib - blocks the epithelial growth factor receptor -Target mores specific genes invoveld in cancers. Select cells with resistant mutations

cancer and immune system outcomes

Elimination - fate of most tumors Intrinsic - tumor-repressor genes -p53 Extrinsic - recognition and killing; innate and adaptive -Immune system can recognize and kill inappropriate cells Controlled -Escape, but remain small Escape and progression to cancer -Immune system inhibited or ineffective Most tumors are eliminated and small are controlled and even smaller number escape and progress to cancer

Somatic mutations: risk depends on tissue

Environmental exposure Lungs, intestine, skin Presence of mitotically active cells -Each cycle of mitosis - opportunity for mutation -Endometrium versus fallopian tubes -Secretory tissue versus muscle -Brain and bone cancers - children more susceptible -A lot of brain and bone growth when younger.

hallmarks of cancer

Escape cell cycle control Suppresses programmed cell death Can divide indefinitely (stable telomeres) Increased mutation rates Acqure characteristics of normal tissues (angiogenesis) so it can get own nutrients Late stages- metastasizes

Evolution and cancer

Evolutionary insights have revolutionized thinking about cancer Susceptibility influenced by trade-offs Clonal selection and phylogenetics Resistance to chemotherapy

Targeted immunotherapy

Exploits existing capacity of the immune system -Stimulating cytotoxic T cells (can attack cancer cells) -Suppressing immune-repressive cells Activate T cytoxic cells and inactivate immuno repressive cells Remove T cells, select clones that specifically react with the cancer, amplify, reinject -Successes and failures with it Most promising current approaches: based on blockade of inhibitory receptors CTL4A and PD-1 -Normally prevent autoimmune attacks

Exploration of alternative therapies to slow evolution or resistance: in terms of chemotherapy and resistant cancer

Exploration of alternative therapies to slow evolution or resistance Targeted immunotherapy Adaptive therapy (managing therapy.) Interventions that target production of public goods

genes involved in cancer

Function in early embryogenesis Mediate cell proliferation, survival, adhesion, migration Silenced during terminal differentiation in most tissues Oncogenic mutations disrupt the epigenetic silencing -Antagonistic pleiotropy -inherited predispositions to cancer: if you inherit mutation at p53 then higher risk for cancer. Cannot eliminate - instead reinforced controls Mechanisms to detect and correct or eliminate cells with oncogenic mutations

Somatic mutations: not all dangerous

Gene: only about 1% of genes are involved in oncogenesis Cell type: most dangerous mutations occur in stem cells Timing: mutations early in development most important -Timing: a lot of this is just change, if you get mutation at p53 at 4 or 5 then higher risk and mutations have to build on each other since you have more time for further development from age 4 or 5. Mutation happening at 70 wont be as important.

cancer evolution: genetic variation Barretts esophagus -> esophageal cancer graph

Genetic variation helped predict which patients would develop cancer # of clones Shannon index of diversity Genetic divergence of clones study that did when you had premalignant tumor. looked at genetic diversity. Red line is patients who had most genetic diversity: higher risk of getting esophageal cancer. which was higher on graph Blue lower genetic diversity which was lower on graph.

cancer phylogenetics: evaluating therapies NSAID graph

Here: had some people that were presecribed NSAIDS for heart disease.then some patients that are on nasaids are later on diagnosed with canver and some have taken nsaids and some havent. Can resconstruct phylogenetic history, can time certain points in a tree and can put wehre they took nsaids and can compare the mutation rate. Looked at the before and after they were taking nsaids just by using phylogenetic way to look back at time When on NSAIDS then lower rate of mutations. NSAIDS could decrease the rate of somatic mutaitons. NSAIDS are anti-inflammatory. Inlfamation can increase somatic something Can compare evolution before and after the treatment

Cancer evolution: genetic variation

Key genes involved in cancer - p16 and p53 Control the cell cycle and DNA repair p16: inhibits CDK4 and CDK6 - important for cell cycle initiation p53: transcription factor (turning off and on multiple genes) : Regulates cell cycle Activates DNA repair proteins Arrest cell cycle when there is DNA damage Initiate apoptosis if DNA damage cannot be repaired More than half of human cancers - mutation of p53 Damage to DNA repair -> increased mutation rate Generates genetic variation Genetic variation (UP) -> Probability of progression to malignancy (UP)

Cancer prevalence

Lifetime risk of cancer in US: 33% Breast cancer in women: 12% Autopsies -Many covert malignant cancers and premalignant neoplasms All adults have thousands of precancerous mutant clones If we lived long enough, we would probably all get cancer (basically everyone has precancerous cells in body, its just a matter of time)

cancer and aging

Maintenance is not perfect -Can put to either maintenance or reproduction and will put to maintenance since that increases reproduction success. -decreases over time. Selection is weaker on the aged than on the young Antagonistic Pleiotropy Accumulation of mutations People are living longer See more cancer and dementia

Multicellular covenant

Multicellularity - 1 billion years ago Stabilized by a fundamental covenant: Somatic cells stop reproducing Germ cells propagate genes Stem cells repair tissues Cancer breaks that covenant

Cancer and stem cells

Multicellularity -> stem cells Great innovation - allow maintenance of tissues Self renewal capacity and potential to differentiate -Preadapted to cancerous lifestyle Positioned all over the body Lungs Intestine Skin Bone marrow

Clonal evolution and cancer

Mutation A happens and those cells proliferate. Mutation b and c get out competed. AB is really good and outcompetes A then C comes in so ABC is the most competitive per say. Order in which mutations evolve can be important. When C evolved on baseline of A then it wasn't that good but when A and B occurred then it was good. Some mutants arise and then die out then mutation happens in p16 so this oen starts to take off then mutation in p53 and that starts to take off so then another mutation in p16 and that takes off. Then another mutation in p53 and that takes off then leads to cancer Red circles: dragger mutation; all cancers may have that mutation Getting bigger since tumor is getting bigger and then can have one metastasis and show up somewhere else. Evolve by clonal selection and each one of these colors is a clone. You have clones replacing one another.

natural killer cells (NK)

NK cells: they don't have to be primed by antibodies and can react to pathogens and tumors without priming to antibodies. Can be triggered by many things. If healthy cell experiences DNA damage or tumor transformation and it will be stressed and NK cells can attack the stress cells. Important sicne an mechanism where it can attack self cells since doesn't need antigen or receptor to recognize it. Activity of NK cells: sophisticated activation. Not wanting to attack self. They have both activating and inhibiting receptors that trigger to kill and keep them from doing it. MHC I receptors: if seen on cells then wont attack those cells. Down regulated Might start downregulating MHC I cells. Cancer cells stop expressing that. If you do that then you get rid of inhibitory aspect and then it comes to attack you. Stress signals will activate NK cells. NK cells are best for attacking cancer cells. Cancer cells try to down regulate MHC I which inhibit so NK cells attack. Activated by cell stress and inhibited by MHC I

cancer and NK cells

NK receptors provide targets for disruption One acute myeloid leukemia -Cancer disrupted NK communication with dendritic cells -Also induced TREG cells to inhibit NK cells

why do somatic mutations occur?

Numbers game Base mutation rate: low, but appreciable - allows evolution to occur 10^-9 mutations per nucleotide per cell division 3.3 billion nucleotides copied each time a human cell divides More than 10^16 cells per individual per lifetime Greater than all the individual humans who have ever lived Opportunities for dangerous somatic mutations are immense DNA experiences damage -UV light, tobacco smoke -Free radicals due to inflammation -Chronic exposure worse than acute Inactivation of genes such as p53 -Genomic instability -> increased mutation rate-> increase liklihood that you end up with cancer

Efficacy of chemotherapy as a selective agent

Patient with late-stage cancer that is metastasizing Surgery considered ineffective Start cytotoxic chemotherapy Tumor shrinks, even disappears from MRI A few months later, tumor reappears Using same drug has no effect Try a different drug, cycle repeats This is exactly how we would select for resistance in the laboratory!

Cancer phylogenetics: what can it tell us?

Process may have started decades ago: first mutation may have started 20 years ago. By the time we are treating it then it has already been there a while. Some convergent evolution - potential for general therapies But also much heterogeneity - challenge for general therapies

Cancer: early origins

Seven individuals who died from pancreatic cancer Sequenced clones from metastases Tumors initiated at least 18 years before death Some evidence of local adaptation in metastases Isolated metastasis from the individuals Lung and liver are metastases and they sequence these clones Start with normal cel and there is intial mutation which starts into tumor cell and then you get parental clone Purple is primary tumor evolution which happened over 12 years then they saw new clones started to evolve that had metastasis ability, happened around 7 years before it got moved to liver. Main point: By the time youre starting to diagnose what is happening, it has already been happening for 15 years or so.

cancer evolution

Short sighted and selfish -evolution is short sighted and selfish since kills in the end and cancer cells die. Rapid but rough - 40-50 generations -a lot of competition to reproduce the most but at the end they all die. Ability to evade or ignore the immune system Metastases adapt to the tissues they invade Originate through mutations -need genetic variability for natural selection to act. Compete for space and resources -ones that are selected for are most cancerous.

why is cancer risk so high for humans?

Significant period of post-reproductive life Highly invasive placentas produced by embryonic stem cells -If turn those genes on again then Ability to move through tissues, establish in new sites -Trade off, important but has high cost Risk factors produced by civilization Reproductive cancers -> by-products of our unique sexuality -Continuous cycling, receptivity, and activity -Continuous tissue proliferation and cell division ex: every time you have a period then you have tissue proliferation.

cancer evolution: genetic variation

Somatic cell evolution mirrors evolution in the germline -Evolution in germline: we draw phylogenetic tree and we are talking about germline mutations that can be passed on to next generations Somatic mutations cant be passed Somatic cell variation: Point mutations EX: SNPS Epigenetically (gene silencing) -no longer silencing genes that should be Cytogenetically: number of chromosomes; can have a lot more than suppose to. Mosaic genetic pattern unique to each individual

Neoplasms evolve by natural selection

Somatic mutations -> variation among clones Variation among clones -> competition Competition -> cancer -Favors clones that can grow fast, disperse, and invade

Cancer and T cells

TREG cells suppress autoimmune responses -inhibit cells that would attack self T reg cells suppress autoimmune responses. NK cells can attack self since they don't need antibodies just attack things that appear stress. Treg suppresses self attack Tumor cells secrete a cytokine (TGF-𝝱): T cells -> TREG cells Tumor cells down regulate expression of MHC I Avoid attack by cytotoxic T cells Too much - attacked by NK cells 2 mechanisms 1. Can turn Tcells into tReg cells which suppresses immune response to self. 2. And influencing expression of MHC I

cancer and immune system: summary

Tumors evolve to suppress or evade the immune system Disable NK cells Subvert the immune response (T cells -> TREG cells) Down regulate expression of MHC-I molecules Change metabolism to modify local microenvironment Resemble pathogens in their manipulative capacity -immune system puts similar selective pressures on pathogens as cancer

cancer and phylogenetics

Use phylogenetics to reconstruct the history of a cancer patient Sequence colonial lineages and reconstruct their history Can start out with normal cell that start to evolve by diff mutations and then two colonial mutations and so on Some lineage can give rise to metastasis

Clonal evolution and genetic diversity

What should be the outcome of clonal evolution? One clone wins? Eliminates others? Clonal evolution: if you take a slice at any one time you expect there to be one clone at that put that arises and does very well and sweeps to fixation. One clone wins, the best competitor that will eliminate all the others. Mestasistis is genetically uniform but this is not the case Not usually the case - why? -Not enough time -Spatially diverse environment - niches in which clones can hide from competition Have one progenitor that give rise to all these different genotypes in the tumor. We don't see one winner. What are the processes that keep this from happening? Maybe there isnt enough time. Maybe before one rises something else rises and then that one goes to sleep Our body can be a spatially diverse environement. Maybe certain colonial lineage does well in one lineage then the other. Clone A can work best in this part of the tumor and clone B can work best in another part of the tumor. MORE ON SLIDE

Clonality

group of cells descent from a single progenitor cell

Cancer over time (graph)

incident rate is pretty constant. Lung and bronchial are most prevalent. Mortality rate due to cancer has not changed as much. -since we are better at treating diseases of cardio then now we are seeing things like cancer and degenerative diseases. if we figure out cancer and degenerative then there is something else.

Neoplasms

masses of abnormal cells: Benign - localized and remain so Premalignant - do not invade and destroy, but can develop that capacity Malignant - undergo metastasis: can disperse, invade, and colonize

what is cancer?

uncontrolled growth and spread of abnormal cells. can be malignant or benign. family of diseases; not a single disease.