Cancer Biology Notes

Cancer as a Microevolutionary Process

• Cancer cells disregard basic rules of cell behavior, providing insights into normal cellular processes.
• Cancer research enhances understanding of cell signaling, cell cycle, apoptosis, tissue architecture, and offers tools for treatment.
• The body operates as a cooperative ecosystem of cells; somatic cells sacrifice themselves for germ cells to propagate genes.
• Multicellular organism cells collaborate, using extracellular signals for social control, cells act appropriately (resting, growing, dividing, differentiating, dying) for the organism's benefit.
• Mutations can disrupt harmony, giving a cell selective advantage, leading to a mutant clone.
• Cancer involves repeated mutation, competition, and natural selection.
• Cancer is a disease where a mutant clone prospers at the expense of neighbors, eventually destroying the cellular society.

Cancer Cells Bypassing Normal Proliferation Controls

• Cancer cells defined by uncontrolled reproduction and invasion/colonization of other territories.
• Uncontrolled growth and proliferation leads to a tumor (neoplasm).
• Benign tumors are non-invasive, complete cure possible by local removal.
• Malignant tumors (cancer) are invasive, spreading to other tissues.
• Invasiveness allows metastasis—secondary tumors forming at other sites, making eradication harder.
• Metastases are generally what kill cancer patients.
• Cancers classified by tissue and cell type of origin.
  • Carcinomas: Epithelial cell cancers, most common (~80%), related to cell proliferation rate and exposure to damage.
  • Sarcomas: Connective tissue or muscle cell cancers.
  • Leukemias/Lymphomas: White blood cell cancers.
  • Nervous System Cancers.
• Benign tumor names exist in parallel with malignant ones (e.g., adenoma vs. adenocarcinoma, chondroma vs. chondrosarcoma).
• Cancer characteristics reflect origin (e.g., basal-cell carcinoma making cytokeratin, melanoma making pigment).
• Different cell types cancers are distinct diseases, with varying malignancy and metastasis potential.
• Classifying cancers by mutations is an alternative approach crucial for treatment design.

Cancer Derivation and Development

• Most cancers originate from a single primary tumor traced back to a single abnormal cell.
• Additional changes accumulate, allowing cells to outgrow/out-divide neighbors.
• Typical cancers develop for years, containing a billion+ cells at detection.
• Tumors contain fibroblasts, inflammatory, and vascular endothelial cells.
• Clonal origin proven by molecular analysis of tumor cell chromosomes: Philadelphia chromosome in CML.
• CML translocation site is identical within a patient but varies slightly between patients.
• This translocation promotes CML by creating a hybrid gene that promotes cell proliferation.
• Most cancers originate from a single aberrant cell.

Somatic Mutations and Cancer

• Tumor cells contain somatic mutations - detectable abnormalities differentiating them from normal cells.
• Cancers driven by epigenetic changes, persistent heritable changes to gene expression.
• Somatic mutations altering DNA are fundamental and cancer is, in this sense, a genetic disease.
• Carcinogenesis (cancer generation) linked to mutagenesis (DNA sequence change).
  • Chemical carcinogens cause nucleotide sequence changes.
  • Radiation (X-rays, UV light) causes chromosome breaks/translocations or base alterations.
• Inherited defects in DNA repair increase cancer risk (e.g., xeroderma pigmentosum and UV damage).
• $10^{16}$ cell divisions occur in a human lifetime, $10^{12}$ in a mouse.
• Mutation rate is $10^{-6}$ per gene per cell division due to DNA replication/repair limitations.
• Every gene is likely to have undergone mutation $10^{10}$ times in a human lifetime, $10^{6}$ in a mouse.
• Cancer is infrequent, suggesting that a single gene mutation is not enough to convert a normal cell to a cancer cell.
• Cancer requires multiple independent genetic and epigenetic accidents.
• Cancer incidence increases with age, suggesting the accumulation of mutations over time.

Gradual Cancer Development

• For cancers with external causes, the disease appears long after exposure (e.g., lung cancer and smoking).
• During the long incubation, prospective cancer cells undergo a succession of changes.
• Tumor progression involves the gradual accumulation of mutations.
• CML begins as nonlethal overproduction of white blood cells, then changes into a rapidly progressing illness.

Tumor Progression

• Cancers arise via cycles of random inherited change and natural selection.
• Tumors grow in fits and starts as advantageous inherited changes arise.
• Tumor progression takes years, involving chance, leading to other causes of death.
• At each stage, cells acquire changes giving them a selective advantage.
• Environmental harshness may be present. Cells may face low oxygen, scarce nutrients, surrounding tissue barriers.
• Larger tumor number leads to higher chance of changes favoring growth.
• Offspring of best-adapted cells divide, producing dominant clones and species often occurs: Original cancer cell lineage diversifies to give genetically different subclones of cells. These may coexist or may colonize separate environments according to their quirks. As new mutations arise within each tumor mass, different subclones may gain an advantage and come to predominate.

Genetic Instability

• Human cancer cells accumulate genetic changes rapidly and are genetically unstable.
• Instability varies among cancers and patients.
• Many cancers have abnormal sets of chromosomes with duplications, deletions, and translocations.
• Chromosomal disruption evolves rapidly in culture.
• Abnormal cell nucleus appearance identifies and classifies cancer; can contain heterochromatin.
• Epigenetic changes of chromatin structure contribute to cancer.
• Genetic instability arises from defects in DNA repair or replication error correction.
• Alterations lead to DNA sequence changes, translocations, and duplications.
• Defects in chromosome segregation cause chromosome instability/karyotype changes and can speed the evolution of malignancy.

Altered Control of Growth

• Mutability and population size allow mutations; selective advantage drives cancer development.
• Mutations increase proliferation rate or enable continued proliferation.
• Cancer cells in culture show a transformed phenotype with abnormal shape, motility, and growth factor responses.
• Transformed cells divide even in suspension and continue moving/dividing after confluence, piling up.
  Normal cells require positive signals; transformed cells no longer require all of them.
• Cancer cells in the body have altered sugar metabolism.
  • Normal adult tissue cells fully oxidize glucose to $CO_2$.
  • Growing tumors need nutrients for macromolecule production.
  • Tumors have metabolism like growing embryos.
  • Tumor cells consume glucose avidly, up to 100x faster than neighbors.
  • Little glucose used for ATP production by oxidative phosphorylation; much lactate is produced.
  • Carbon atoms from glucose are diverted towards small molecule production for protein, nucleic acids, and lipids.
• Warburg effect - tumor cells de-emphasize oxidative phosphorylation, instead taking up large amounts of glucose, even when oxygen is plentiful. This promotes cancer cell growth.
• High glucose uptake allows tumor imaging.

Ability to Survive Stress

• Multicellular organisms have mechanisms guarding against damaged cells.
• Internal disorder gives danger signals, activating apoptosis.
• Cancer cells require mutations to elude defenses against misbehavior.
• Mutations drive the cell into an abnormal state, metabolic processes are unbalanced and homeostasis is inadequate.
• States of this type are loosely referred to as cell stress.. Chromosome breakage and DNA damage are typical.
• To divide without limit, a prospective cancer cell must accumulate mutations that disable the normal safety mechanisms.
• Cancer cells fail to undergo apoptosis when a normal cell would.
• Cell death occurs on a massive scale inside large solid tumors, more by necrosis than apoptosis.
• Tumor grows because cell birth rate outpaces cell death rate, but often by only a small margin.
• Tumor doubling time can be far longer than tumor cell cycle time.
• Many normal human cells have built-in division limit.

Built-In Limit to Cell Proliferation

• Human cancer cells avoid replicative cell senescence, can maintain telomerase activity, so that telomeres do not shorten or become uncapped, or they can evolve an alternate mechanism based on homologous recombination (called ALT) for elongating their chromosome ends..
• Tumor microenvironment influences cancer development.
• Tumor development relies on two-way communication between tumor and stroma.
• The stroma provides a framework for the tumor and is composed of normal connective tissue, fibroblasts and inflammatory white blood cells, as well as the endothelial cells that form blood and lymphatic vessels with their attendant pericytes and smooth muscle cells. As a carcinoma progresses, cells secrete signal proteins, modify ECM, while stromal cells stimulate cancer cell growth/division and remodel ECM.

Surviving in Foreign Environment

• Cancer cells need to spread and multiply at new sites (metastasis).
• This is the most deadly aspect, responsible for 90% of cancer-associated deaths.
• Metastasis is a multi-step process: cells invade local tissues/vessels, move through circulation, leave vessels, establish colonies.
• Cells must break free of constraints, invasiveness is one of defining properties of malignant tumors.
• Tumor cells must penetrate blood/lymphatic vessels (lymphatic allow entrance in clumps) in a process resembling EMT (epithelial-mesenchymal transition).
• Circulating tumor cells (CTCs) can be detected as a minute blood sample.
• Only a tiny proportion of cells successfully exit, settle, survive, and proliferate.
• Colonization is most difficult: migrant cells may fail to survive, or may only thrive for a short while and found a micrometastasis that then dies out.
• Many cancers are discovered before metastatic colonies established.

Properties Contributing to Cancer Growth

• To produce a cancer, a cell must acquire a range of aberrant properties
• The key attributes of cancer cells include:
  • They grow (biosynthesize) when they should not, aided by a metabolism shifted from oxidative phosphorylation toward aerobic glycolysis.
  • They go through the cell-division cycle when they should not.
  • They escape from their home tissues (that is, they are invasive) and survive and proliferate in foreign sites (that is, they metastasize).
  • They have abnormal stress responses, enabling them to survive and continue dividing in conditions of stress that would arrest or kill normal cells, and they are less prone than normal cells to commit suicide by apoptosis.
  • They are genetically and epigenetically unstable.
  • They escape replicative cell senescence, either by producing telomerase or by acquiring another way of stabilizing their telomeres.

Cancer-Critical Genes

• Cancer depends on inherited changes in somatic cells.
• Identify mutations and epigenetic changes, discover how they give rise to cancerous cell behavior.
• Cancer Genome Project has identified a wide range of mutations within a cancer cell.
• Genes altered are called cancer-critical genes.
• Cancer-critical genes grouped by activity: too much or too little.
• Proto-oncogenes: Gain-of-function mutation drives cells towards cancer; mutant forms are called oncogenes.
  Tumor suppressor genes: Loss-of-function mutation contributes to cancer.
• Somatic mosaicism: alterations result in genomic instability; subclass of cancer-critical genes: sometimes called genome maintenance genes.
• Overproduction of a signal for cell proliferation can result from either kind of mutation.

Identification of Cancer-Critical Genes

• Oncogene mutation has dominant, growth-promoting effect on cell.
• Oncogene identified by its effect when added.
• Tumor suppressor gene cancer-causing alleles are generally recessive; both copies must be removed/inactivated.

Retroviruses

• Search for genetic causes of human cancer through study of tumor viruses.
• Retrovirus RNA genome copied into DNA, inserted into host genome.
• DNA inserted by Rous sarcoma virus made host cells cancerous.
• v-Src, a gene the virus picked up, was unnecessary for the virus; similar to c-Src in vertebrate genome.
• c-Src had been caught accidentally, underwent mutation to become an oncogene (v-Src).

Gene—Ras

• Other searches identified human cancer cell oncogenes, fragments provoking uncontrolled proliferation.
  Mouse fibroblast Tester cells: previously selected for their ability to proliferate indefinitely.
• DNA fragments introduced into cultured cells; colonies of abnormally proliferating cells appeared.
  Each colony was a clone containing a DNA fragment that drove cancerous behavior, containing a human version of the already-known rat tumor retrovirus oncogene, v-Ras genes.
• Normal Ras are monomeric GTPases transmitting signals from cell-surface receptors.
• Ras oncogenes contain point mutations creating hyperactive Ras protein that cannot shut itself off.
• Effect is dominant; one gene copy needs to change.
• ~30% of human cancers have mutated Ras family members.

Cancer Gene Mutation

• Proto-oncogene becomes oncogene via:
  • DNA sequence change (point mutation/deletion) producing a hyperactive protein, or protein overproduction.
  • Gene amplification leads to overproduction.
  • Chromosome rearrangement changes protein-coding/control regions.
• EGF receptor can be activated by deletion, causing constant activity, mutation found in glioblastoma.
• Myc protein (stimulating growth/division) generally contributes to cancer by overproduction. Translocation in Burkitt's lymphoma brings Myc gene to those that normally drive the expression of antibody genes in B lymphocytes.

Tumor Suppressor Genes

• Key insight: study of tumor retinoblastoma, cancer rare type caused by small number of mutations.
• Retinoblastoma occurs in childhood: Tumors develop from neural precursor cells in the immature retina one in 20,000 has it. One hereditary and the other not.
  • Hereditary: Multiple tumors, in both eyes.
  • Non-hereditary: One eye is infected, by only one tumor.
• Some retinoblastoma cases have abnormal karyotype, a deletion in chromosome 13 predisposing to disease.
• Deletions in chromosome 13 also found in non-hereditary, suggests cancer caused by loss of critical gene there.
• The Rb gene encodes a universal regulator of the cell cycle present in almost all cells of the body (see Figure 17–61).
• Missing in lung, breast, and bladder carcinomas, important in progression to malignancy.

Genetic, Epigenetic Mechanisms

• Tumor suppressor genes - inactivation is dangerous, occurs with various combinations.
• 1st copy: chromosomal deletion / point mutation.
• 2nd copy: chromosome loss due to errors. gene replacement by a mutant version through mitotic recombination or gene conversion. DNA sequence change.
• Epigenetic: Packaging into heterochromatin and/or C nucleotides in CG sequences silenced in a heritable manner, common in tumor progression.

Sequencing of Cancer Cell Genomes

• Cancer cell genomes scanned systematically: tumor's complete genome sequence; exome (protein coding genes); genomic region analysis.
• Surveyed for: Epigenetic changes, and levels of gene expression via mRNA analysis.
• Comparing cancer cells vs. non-cancerous with same patient.

Disrupted Genome

• Degree of genetic disruption varies, both in severity and in character.
• Some cases: The karyotype is normal, but many point mutations are detected in individual genes.
• Chromosome maintenance, cell-cycle checkpoints, and/or DNA repair - suggest failure here. breast cancers example.
  DNA-avoidance machinery and DNA double-strand breaks appear defective, with progressive increase. This extreme hard to treat, with a hard prognosis.
• Whole-genome analysis explains retinoblastoma (tumor cells contain loss-of-function mutations in the Rb gene).
  Practically no mutations or genome rearrangements in other tumor suppressor genes, but many epigenetic modifications of its known genes are in one well-analyzed case.

Mutations in Tumor Cells

• Cancer cells contain many mutations beyond chromosome abnormalities, with scattering across the genome, presenting a problem: distinguishing cancer drivers from passengers.
• Frequency determines causal factors, and driver mutations play a part in the disease; passenger mutations are unlikely to be found in the same genes in different patients.
• The human genome is 300 genes critical, that are mostly related to secreted signals, transmembrane receptors, more. and all susceptible for cancer properties.
• Complexity not quite as daunting as may initially seem.

Handful of Key Disruptions

• Some genes (Rb and Ras) are mutated in many/different cancer types that are not a surprise to the fact they control dividing and growth.
  It’s also the mutations in other cancer-critical genes that play into the process.
• Gliabosta is a human tumor good example the genomes showed functions were known so each could be assigned.
  It was noted genes here governed both the initiation of the cell and growth and a DNA damaging system with tumors all involved in mutations.
• Different signaling in tissues also affect them, and have also now to act. At all same genes/processes at once.
  Also to the signals to help fail.

PI3K/Akt/mTOR Pathway Mutation

• Cell growth requires cell growth, anabolic processes synthesizing macromolecules and depends upon proliferation.
  Cell also divides then requires another. signals for growth.
• PI3-kinase/Akt/mTOR intracellular singling pathway is critical for cell growth control. Activated when no signal. Abnormal activation stimulates a supply of the small-molecule building blocks.
• Aberrant rates shown, also with high risks including fat, can all effect too .

P53 Pathway Mutations

• Cancer cells breaking rules, obvious at stress too…
  p53 high gene high in the 5th number. Must review also 1st
  In cell normal conditions there is very low protein since it is destroyed and the mice lacking all usually have it before 10 months.
• cells put danger high with low gene numbers, special conditions including DNA damaging.
  It takes hours here actions taken, can block or recover it. That is what makes this also an apoptosis one can do from another, has good effects all day then has problems it won’t function at all.
  Also those functions and results won’t come from all.

Forms of Genome Instability

• If p53 is functional, unrepaired DNA damage won’t stop cells. P53 is lacking
  In ovarian, an example. breaks commonly correlates here . If there isn’t more scattered too like in the colorectai here at alL. And its also that these issues can bring it about.

Rare to Core Pathways Mutations

• Mutations aren’t the only way to effect core procoes to these signaling in the cell from the pathwaies that are open.
  Prostate, lung. Can all mutate at high percentages now. In prostate gland an androgen testosterone signal also to do .

Mouse Uses

• Mouse test is to know how to do the cancer part with the critical deletion of tumor, you can engineer what and when.
  Mice are the main test to see, with all those experiments.

Mouse Complications

• The test has a very serious menace, because of the high chance cancer will exist from inherited test.
  Cells go high but then later go different and change to survive. Thus needs more to see for a while here now

Cell Diversity

• There tumors differ in the fact cancers all can have genetics, there cell is not the same and is too diverse. Constantly mutating
  To the fact as an example that are many small in the K-Ray, Given more than perhaps would even taken on all. Some more will see a high process and a new area!
• Tumors is a mix, its hard and is very effective!

What Do They Exploit to Live

• As mentioned prior cells cannot all have all.
  They have to escape normal confines and begin to invade beneath though it’s hard to happen so all the processes and cells survive.
• What’s there when is that fact something must be in the way. As we say in our prior notes.
  We look also then later too.

How It All Affect Tissue

• Self is breeding ground . All renew and are renewed. Stem cells that differ.
  Normal stem is in what does ,each dsughter stem, and this choice does what its all needs for maintenance in the long term too.
• The system all works. The fact all know and we keep making new , and is hard at what it does. A small will keep going . Radiation and medicine or something will then keep having the same effect.
• So its going for help from medicine. It causes all easy ones. But then is easy when you use it right because a good method in test to help. Will only then effect those that are good.

Cancer Treatment

• All treatments are needed since is big. They all also are at where at and need the things around help with these issues and side effects and etc.
• Good. All are made not just drugs also! But other. There isn’t a high chance of a full clear.
  Those parts those. Are to be great. If we can then all will be made . Then all those too, should have the best effect!
• As a whole, now can keep from needing, do better! All all make be!

Preventable Cases of Cancer

• Background isn’t one. Is just inevitable since errors happen. They will occur forever .

They high test has it all. Has it that tests are correct. Should all be avoidable by the correct time and conditions

• Test the new one . They are that is has effects and you must also do it in a new test .

Preventable Ways to Combat

• Those also that are all set ! Good test here too!
  Mostly in that case, most not so important. So be in those ways now too that are done here the best way at that for the test.
• Chemicals . Always do it. Or it becomes damaging that now will process it.
  Or make new to do!
• Many bad causes will be . Is best and has those right tools and also will . See that those results.

Drugs/Molecules for Cancer

• New target cancer better a what the right effects do and all helps be done.
  More we use and know these are doing!
  Great . As if in the world. There isn’t high level and its the reason great to to and be to good at medicine because need effects. What is going for, to where and go good for cancer right now
• Is the immune system used right, will kill it by hunting and killing it by antigens
  It’s been learned the correct systems will be tested and not harm people!
  As is being done here.

Resistance Strategy

• Some test and all are always not good results. More test that those that show good will
  Those good for it that keep , then a good medicine effect or do some more test and use the right method and be that too . The tumor will often reduce and be fine so great is the process here!
  Those test that may then be . That those is test . Always good since you never know why the last is there.
  MDR1 to be also too!
• Drug high and all will test good right all those . There’s no more we help that’s the facts we did.
  We are going and need the new way that great to know, will test correct so to get good too , not bad.
  Summary
  mThe molecular analysis of cancer cells reveals two classes of cancer-critical genes: oncogenes and tumor suppressor genes. A set of these genes becomes altered by a combination of genetic and epigenetic accidents to drive tumor progression. Many cancer-critical genes code for components of the social control pathways that regulate when cells grow, divide, dierentiate, or die. In addition, a subclass of tumor suppressors can be categorized as “genome maintenance genes,” because their normal role is to help maintain genome integrity.
  mThe inactivation of the p53 pathway, which occurs in nearly all human cancers, allows genetically damaged cells to escape apoptosis and continue to proliferate. Inactivation of the Rb pathway also occurs in most human cancers, illustrating how fundamental each of these pathways is for protecting us against cancer.
  mThe sequencing of cancer cell genomes reveals that—except for the cancers of childhood—many cancers acquire 10 or so driver mutations over the long course of tumor progression, along with a considerably larger number of passenger mutations of no consequence. The same methods reveal how subclones of cells arise and die out as a tumor ages. Tumors thus contain a heterogeneous mixture of cells, some—the so-called cancer stem cells—being much more dangerous than others.
  mWe can often correlate the steps of tumor progression with mutations that activate specific oncogenes and inactivate specific tumor suppressor genes, with colon cancer providing a good example. But dierent combinations of mutations and epigenetic changes are found in dierent types of cancer, and even in dierent patients with the same type of cancer, reflecting the random way in which these inherited changes arise. Nevertheless, many of the same changes are encoun- tered repeatedly, suggesting that there are a limited number of ways to breach our defenses against cancer.Cancer Prevention and Treatment: Present and Future
  mOur growing understanding of the cell biology of cancers has already begun to lead to better ways of preventing, diagnosing, and treating these diseases. Anticancer therapies can be designed to destroy cancer cells preferentially by exploiting the properties that distinguish cancer cells from normal cells, including the cancer cells’ dependence on oncogenic proteins and the defects they harbor in their DNA repair mechanisms. We now have good evidence that, by increasing our understanding of normal cell control mechanisms and exactly how they are subverted in specific cancers, we can eventually devise drugs to kill cancers precisely by attacking specific molecules critical for the growth and survival of the cancer cells. In addition, great progress has recently been made through sophisticated immunological approaches to cancer therapy. And, as we become better able to determine which genes are altered in the cells of any given tumor, we can begin to tailor treatments more accu- rately to each individual patient.