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Questions and Answers
What percentage of breast cancers are accounted for by BRCA1 and BRCA2 mutations?
What percentage of breast cancers are accounted for by BRCA1 and BRCA2 mutations?
Tamoxifen has been shown to increase breast cancer incidence in high-risk women.
Tamoxifen has been shown to increase breast cancer incidence in high-risk women.
False
What is the typical impact of loss of contact inhibition in cells?
What is the typical impact of loss of contact inhibition in cells?
Cells lose the ability to undergo apoptosis and grow uncontrollably.
The length of time between disease detection and usual clinical presentation is known as __________.
The length of time between disease detection and usual clinical presentation is known as __________.
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Match the color of circles to their corresponding cancer cell characteristics:
Match the color of circles to their corresponding cancer cell characteristics:
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What is one of the major results of losing adhesion molecules in breast cells?
What is one of the major results of losing adhesion molecules in breast cells?
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Hereditary breast cancers can generally be screened effectively.
Hereditary breast cancers can generally be screened effectively.
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What happens during the RAS pathway activation related to oncogenes?
What happens during the RAS pathway activation related to oncogenes?
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What is the primary role of angiogenesis in cancer progression?
What is the primary role of angiogenesis in cancer progression?
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Most cancers metastasize exclusively through blood vessels.
Most cancers metastasize exclusively through blood vessels.
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What is adjuvant chemotherapy used for?
What is adjuvant chemotherapy used for?
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The protein _______ on tumor cells prevents T cells from binding and killing cancer cells.
The protein _______ on tumor cells prevents T cells from binding and killing cancer cells.
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Match the following chemotherapy treatments with their descriptions:
Match the following chemotherapy treatments with their descriptions:
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What phenomenon occurs when cancer cells travel to distant organs and remain inactive?
What phenomenon occurs when cancer cells travel to distant organs and remain inactive?
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Which step indicates a loss of cell junctions in the progression to cancer?
Which step indicates a loss of cell junctions in the progression to cancer?
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Tumor suppressor genes help prevent uncontrolled cell proliferation.
Tumor suppressor genes help prevent uncontrolled cell proliferation.
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What is the term for the state in which a cell permanently stops dividing but remains metabolically active?
What is the term for the state in which a cell permanently stops dividing but remains metabolically active?
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Acquisition of the ______ phenotype is key to metastasis.
Acquisition of the ______ phenotype is key to metastasis.
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Match the following terms with their descriptions:
Match the following terms with their descriptions:
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Which of the following factors contributes to the exit from G0 phase and entry into the cell cycle?
Which of the following factors contributes to the exit from G0 phase and entry into the cell cycle?
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What is lead time bias?
What is lead time bias?
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Cancer cells activate telomerase to maintain telomere length.
Cancer cells activate telomerase to maintain telomere length.
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What sequence do human telomeres consist of?
What sequence do human telomeres consist of?
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The enzyme responsible for synthesizing telomeres is called __________.
The enzyme responsible for synthesizing telomeres is called __________.
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Which proteins are involved in mediating cell entry into senescence?
Which proteins are involved in mediating cell entry into senescence?
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Normal cells are motile and can migrate like cancer cells.
Normal cells are motile and can migrate like cancer cells.
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What are the four steps of cancer cell motility?
What are the four steps of cancer cell motility?
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Matrix metalloproteinases (MMPs) help degrade the __________.
Matrix metalloproteinases (MMPs) help degrade the __________.
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Match the terms with their descriptions:
Match the terms with their descriptions:
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What happens to normal cells after repeated divisions?
What happens to normal cells after repeated divisions?
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Study Notes
Eight Steps for a Cell to Become a Cancer Cell
- Loss of Tumor Suppressors: Cells normally grow in the G1 phase of the cell cycle. Genes such as P16, p21, and RB1 prevent cells from moving to the S phase if mutations are detected. These genes trigger repair mechanisms if a mutation is found.
- Loss of Polarity: Mammary epithelial cells lose their normal symmetry and begin to spread within cell ducts due to a lack of cell junctions. This is known as hyperplasia.
- Loss of Proliferative Control: Breast cells normally only divide when indicated by hormones or external factors. These cells normally sit in the G0 phase.
- Decreased Ability to Undergo Apoptosis: DNA repair genes are inactivated, leading to the evasion of apoptosis.
- Loss of Senescence: Cells are unable to divide an infinite number of times. Senescence is a state where a cell permanently stops dividing but remains metabolically active. Telomeres at the end of chromosomes shorten with each division, leading to senescence. However, cancer cells activate telomerase or use alternative mechanisms to maintain their telomere length, allowing them to bypass senescence.
- Acquisition of Invasive Phenotype: Cancer cells become motile and can invade surrounding tissues with the help of Matrix Metalloproteinases (MMPs). These proteins degrade the extracellular matrix, aiding in metastasis and angiogenesis.
- Acquisition of Angiogenic Phenotype: Tumors require a sufficient blood supply to grow and metastasize. Proangiogenic factors, such as Vascular Endothelial Growth Factor (VEGF), promote blood vessel growth.
Tumor Suppressors and Susceptibility Genes
- Tumor suppressor genes can be mutated, allowing for uncontrolled cell proliferation.
- Susceptibility genes increase an individual's predisposition to developing a certain disease or disorder.
Hereditary Breast Cancer
- Some breast cancers are hereditary and cannot be screened for.
- Individuals with first-degree relatives who have had early breast cancer have a higher incidence (up to 25%).
- BRCA1 and BRCA2 genes account for only 5% of breast cancers but are associated with a 95% lifetime probability of developing breast cancer in positive patients.
- Screening for BRCA1 is only practical in patients with relatives who are BRCA positive.
Breast Cancer Prevention
- A trial demonstrated a 49% reduction in breast cancer incidence in high-risk women taking tamoxifen compared to a placebo.
- Tamoxifen effectively decreases breast cancer incidence in at-risk women.
Loss of Symmetry and Polarity
- Normal cell ducts have nuclei lined up around the ducts. Cells sit at the basement membrane and are tightly packed.
- In benign hyperplasia, cells grow uncontrollably into the ducts.
- Loss of adhesion molecules disrupts the cell membrane and basement membrane. Tight junctions that maintain cells shoulder to shoulder are no longer present.
Loss of Proliferative Control
- Loss of contact inhibition allows cells to continue dividing without normal growth constraints.
- Atypical cells grow into ducts in combination with normal cells.
Oncogenes
- Oncogenes are turned on and induce the RAS pathway, allowing cells to enter the S phase, leading to cell proliferation.
- Oncogenes are potential targets for gene therapy.
Cancer Development
- Cancer cells evade apoptosis because DNA repair genes are inactivated.
Genetic Progression and the Waiting Time to Cancer
- An adenoma grows from a population of 10^6 to 10^9 cells, accumulating mutations that drive phenotypic changes seen in cancer cells.
- Blue circles represent adenoma cells before accumulating mutations.
- Green circles represent cells that have acquired additional mutations but not enough for malignancy.
- Red circles represent cells with the number of mutations required for the cancer phenotype.
Steps to Carcinogenesis & Lead Time Bias
- Lead time bias is a flaw in many screening trials.
- Lead time is the time between a disease's early detection (based on new criteria) and its traditional clinical presentation.
- Lead time bias occurs when two tests are compared, and one test diagnoses the disease earlier, but there is no effect on the outcome of the disease. This can falsely suggest the earlier test prolongs survival.
Telomerase
- Human telomeres consist of repeats of the TTAGGG/CCCTAA sequence at chromosome ends. These repeats are synthesized by the enzyme telomerase (hTERT).
- Transfection of hTERT into differentiated somatic cells can induce immortalization and prevent senescence.
- Embryos have hTERT, which assists in telomere expansion needed for cell differentiation.
- Normal cells undergo senescence in response to telomere shortening after repeated divisions.
- Many cancer cells activate telomerase to bypass senescence and maintain their telomere length.
Senescence
- Following extensive cell passage (replication) in culture, oncogene activation, or exposure to oxidative damage, primary cultures of mammalian cells will enter into irreversible growth arrest and display the hallmarks of the senescent cell.
- Proteins that regulate senescence include the p16INK4A tumor suppressor and p19ARF, which sequesters MDM2, inhibiting the MDM2-dependent degradation of p53.
- Cancer cells evade the normal process of senescence, which leads to cell cycle arrest and permanent growth cessation.
Acquisition of Invasive Phenotype
- Cancer cells need to be motile to progress.
- Matrix Metalloproteinases (MMPs) are secreted by both tumor and stromal cells to degrade the extracellular matrix, aiding in metastasis and angiogenesis.
Cell Migration
- Normal cells are not motile, while cancer cells are.
- Cancer cell motility occurs in four steps:
- Extension of lamellar pod from the cell body and formation of a cohesion complex.
- Attachment of the cohesion complex to the extracellular matrix.
- Stress fiber formation that polymerizes from the cohesion complex to the back of the cell.
- The cohesion complex at the rear of the cell adheres, moving the cell forward.
Metastasis
- The tumor travels to a secondary site.
- The tumor invades the secondary site.
- The tumor survives at the secondary site, creating a hostile microenvironment.
- The tumor re-expresses adhesion molecules for survival at the new site.
Acquisition of Angiogenic Phenotype
- Angiogenesis, the formation of new blood vessels from pre-existing ones, is crucial for cancer progression.
- Tumors need a sufficient blood supply to grow beyond a certain size and metastasize.
- Mechanisms of angiogenesis include:
- Proangiogenic factors, such as VEGF, promote blood vessel growth.
- A cancer-benefiting microenvironment.
- Vascular count correlates with poor survival rates.
Dormancy
- Cancer cells can travel to distant organs and become dormant.
- Cancer stem cells are dormant.
- The mechanisms of dormancy are largely unknown.
- Most dormant cells never recur, while some die, remain dormant, or recur.
- Recurrence is often treated with adjuvant chemotherapy.
- Chemoresistance may lead to the need for adjuvant trials.
Bone Marrow Metastasis
- Most cancers metastasize through lymph nodes.
- Adjuvant chemotherapy is given to reduce the chances of cancer returning, but micrometastasis of the bone marrow may still be present.
Immune System Targeted Treatment and PD-L1
- Tumors have active anti-immune mechanisms, such as PD-L1 expression on tumor cells.
- PD-L1 prevents antigen-presenting cells from binding to T cells, inhibiting T cell function.
- New cancer treatments inhibit PD-L1, allowing T cell function to resume.
Principles of Chemotherapy
- There are a billion cells in a cubic centimeter. It takes a billion cancer cells to see a tumor on an X-ray.
- A cancer cell divides exponentially.
- A patient will not be aware of cancer until it reaches 10^10 divisions.
Four Ways of Giving Chemotherapy
- Induction Treatment: Used for advanced cancer when no other alternatives are available. Aims to maintain or shrink tumors with minimal side effects.
- Adjunct to Local Methods: Given to decrease chances of cancer recurrence.
- DNA Synthesis Targeted: Antimetabolites target DNA synthesis itself. Alkylating agents target DNA itself.
- DNA Transcription or Duplication Targeted: Intercalating agents target both transcription and duplication of DNA.
- Mitosis Targeted: Spindle poisons target mitosis.
Goldie-Coleman Hypothesis
- Tumor cells acquire spontaneous mutations that result in drug resistance between the 10^3-10^6 cell stage.
- Detectable tumors are at least 10^9 cells.
- Tumors at diagnosis have drug-resistant clones—the number depends on the individual mutation rate.
Combination Chemotherapy
- Single drugs cannot cure cancer. Combination drugs are needed for durable responses.
- Combinations based solely on biochemical actions are ineffective.
- Combination chemotherapy uses effective drugs from different classes that have demonstrated efficacy individually.
Objectives of Combination Chemotherapy
- To provide maximum cell kill within the toxicity range tolerated by each drug.
- To provide a broader range of coverage of resistant cell lines in a heterogeneous tumor population.
- To prevent or slow the development of new resistant clones.
Principles for Selecting Drugs for Effective Combination Chemotherapy
- Select only drugs that have been shown to be partially effective when used alone, preferably ones producing some fraction of complete response.
- When multiple drugs within a class are available, select ones whose toxicities do not overlap with those of other drugs in the combination. This broadens the side effect range but limits lethal side effects to the same organ, maximizing dose intensity.
- Use drugs at optimal doses and schedules:
- Give combinations at constant intervals to avoid allowing for tumor regrowth.
- Maintain the shortest possible inter-treatment interval while allowing sufficient recovery time, usually for bone marrow.
- Omission of a drug from a combination may allow growth of a clone sensitive to that drug but resistant to all others.
- Arbitrary dose reductions may hinder effectiveness.
Complications of Chemotherapy
- Bone Marrow Suppression: Chemotherapy affects bone marrow, which supplies mature cells to circulation for 8-10 days. Nadir blood counts occur 10-14 days after chemotherapy, recovering by 21 days. Colony stimulating factors shorten recovery.
- Pulmonary Toxicity: Some chemotherapy drugs can trigger the formation of superoxide radicals, H2O2, and OH radicals. Other mechanisms include immune activation, collagen deposition, fibrosis, and inactivation of the antiprotease system. Predisposing factors include age, previous radiation therapy to the lungs, high oxygen levels, and decreased creatinine clearance leading to drug retention. Symptoms include dyspnea, "velcro" rales, dry cough, and decreased DLCO.
Complications of Chemotherapy
- Cardiac Toxicity: Anthracyclines are associated with increasing cardiotoxicity with cumulative doses. A lifetime threshold of 550 mg/m^2 exists. Mediastinal radiation therapy increases the risk. Cardiac toxicity can be acute or subacute, resulting in mitochondrial swelling, disruption of myofibrils and sarcoplasmic reticulum, and vacuolization. It can lead to cardiomyopathy, decreased systolic function, and exercise response.
- Chemical Cystitis: Caused by cyclophosphamide (cytoxan) and ifosfamide. Symptoms include frequency, urgency, dysuria, nocturia, microhematuria, and exanguinating hemorrhage. Late sequelae include fibrosis and malignancy. Caused by acrolein, a breakdown product of the drugs. Mesna (2-mercaptoethane sulfonate) complexes with acrolein to neutralize it and prevent toxicity.
- Gonadal Dysfunction: Testicular and ovarian function can be negatively impacted by certain chemotherapy agents. Testicular function is vulnerable to progressive, dose-related depletion of germinal epithelium lining the seminiferous tubules. Clinical manifestations include reduced testicular volume, sperm count, infertility, and increased FSH. Ovarian dysfunction can lead to amenorrhea, post-menopausal symptoms, and elevated LH and FSH. Alkylating agents are particularly damaging to the ovaries, and at least half of women treated with them develop ovarian failure (except children). Adjuvant chemotherapy for breast cancer can also lead to amenorrhea, with worse outcomes depending on age and dose.
Gonadal Dysfunction
- Chemotherapy agents associated with testicular depletion include chlorambucil, cytoxan, busulfan, procarbazine, nitrogen mustard, and nitrosoureas. Probable agents include vinblastine, adriamycin, Ara-C, and cisplatin.
- Chemotherapy agents associated with ovarian dysfunction include cytoxan, busulfan, nitrogen mustard, L-phenylalaninmustard. Unlikely agents include methotrexate, 5-FU, and 6-MP.
- Agents with an unknown effect include adriamycin, bleomycin, vinca alkaloid, cisplatin, nitrosourea, and Ara-C.
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