Lecture 10: Cancer Flashcards
Define neoplasm.
Abnormal mass of tissue produced when cells divide more than they should or do not die when they should.
AKA the tissue/cell is lacking its normal regulatory control.
Define neoplasia.
Process of formation of an abnormal growth.
Define proliferation.
The process by which cells divide and reproduce.
What are the two ways by which cells proliferate?
Meiosis and Mitosis
What mediates cell proliferation?
Gene expression, growth factors, and signaling molecules.
What is the specific kinase that regulates cell division?
mTOR, which also changes depending on local nutrition.
Define differentiation.
The process by which cells are transformed into different and more specialized cells.
What causes a cell to be differentiated?
Gene expression.
Influenced by growth factors and other stimuli
As a cell becomes MORE specialized, is it more or less likely to divide?
Less likely!
Important!!!!!!!!
What are stem cells?
Highly undifferentiated cells with SELF-RENEWAL
They have the potential to divide into multiple types of cells, which will eventually become fully differentiated cells.
What is a progenitor/parent cell? Why is it distinct from a stem cell?
It is still a cell that can divide, BUT parent cells have only a few options to differentiate into.
What are the 5 types of stem cells from most undifferentiated to most differentiated?
Totipotent: ALL CELL TYPES (AKA TOTAL RANGE)
Pluripotent: all adult cell types (PLENTY)
Multipotent: MULTIPLE cell types
Oligopotent: FEW cell types (Oligo means few/scanty)
Unipotent: ONE cell type
What are most progenitor cells in terms of stem cell ranking?
Oligopotent or unipotent.
Define carcinogenesis.
Origin and development of cancerous neoplasms
What kind of cells are most susceptible to neoplasia?
Rapidly dividing, labile cells
What percentage of cancers develop post birth?
95%
Define oncogenesis.
The mechanism by which normal cells BECOME cancer cells.
What is monoclonal origin?
The concept of cancer originating from a single cell with genetic mutations.
What 3 genes are responsible for making sure our cells do NOT develop into cancer?
Mutator genes
Protooncogenes
Tumor suppressor genes.
Define mutator genes.
They help repair mutated DNA and protect our genome.
The repair typically happens POST environmental insult.
Note: We have multiple mutator genes, so it is the failure of MULTIPLE that leads to us accumulating mutations and thus cancer.
Define protooncogenes.
Promote cell growth and development.
Specifically, they are normal genes that code for the proteins that regulate cell growth and differentiation, BUT they can become oncogenes.
Define tumor suppressor gene.
Control apoptosis, regulate cell division.
This is designed to ensure we have the optimal number of cells in our body. Therefore, failure of this gene = uncontrolled cell division = endless growth.
Does a single gene mutation usually cause cancer?
No!
What are the 3 tumor suppressor genes discussed in class? How are they distinct from each other?
TP53 (p53 protein) is found on chromosome 17.
It is often implicated in many colon, lung, and breast cancers.
Regulates apoptosis of CANCER cells post chemo/radiation.
RB Gene (Rb protein) is the first tumor suppressor gene ever discovered.
Associated with retinoblastoma and other cancers.
BCL2 gene (Bcl-2 protein) regulates apoptosis.
Mutation results in a POORER response to cancer therapy.
Often associated with leukemia and other cancers.
What is the two-hit hypothesis?
Example: Retinoblastoma.
Even if a child carries the susceptibility gene for retinoblastoma, that is only 1 of the 2 chromosomes.
The susceptible child needs just 1 mutation to get retinoblastoma.
However, for someone not born with the gene, they need 2 individual mutations to get retinoblastoma, hence two-hit.
Note: See slide 19 for a visual.
How do protooncogenes mutate? What do they become?
They become oncogenes via 3 methods:
Point mutation: damage of a single nucleotide pair (usually spontaneous or from environment)
Chromosomal translocation: chromosome breaks, relocates, and unites with another chromosome.
Gene amplification: accelerating replication of genes, leading to overproduction of proteins associated with that gene.
Define oncogenes.
Genes that promote UNregulated cell growth and development, inhibit cell death.
They encode growth factors to promote cell division.
Disturbing cell surface receptors and cell-to-cell communication.
Encoding proteins to alter cell cycle, restrict apoptosis, and impact differentiation.
How do I name an oncogene?
Viral ones = v, like v-src
Cellular ones = c, like c-neu
What are some general types of genetic mutations for chromosomes?
Duplication, Inversion, Deletion, Insertion, Translocation.
See slide 22 for visual.
What two events are required for a tumor to be called cancer?
Initiating event
Promoting event
Define initiating event and what cells are most susceptible.
Initiating events are the event that causes a mutation in a cell. This is usually caused by a carcinogenic agent or a sporadic mutation.
The cells most susceptible are the ones actively synthesizing.
Define promoting event and a common cause.
It is the event that causes the cell to actively grow and reproduce more.
Most commonly caused by chronic inflammation.
Also, complete carcinogens can do both initiation and promotion of neoplastic transformation.
Define Progression in terms of cancer.
Extension of promotion phase.
Important:
Cell no longer requires the promoter to be present AND
Cell acquires ability to invade tissue, metastasize, and grow autonomously.
Why is a functional immune response essential to prevent cancer?
A functional immune response allows us to fight many cancers, because most cancers express abnormal HLA-1 antigens that our body can still recognize and defeat.
Immunosuppressed patients have higher rates of cancer as a result.
What are the host factors that affect cancer susceptibility?
Immunologic response
Age
Chronic Inflammation
Genetic Predisposition
Genetic Disease
Hormones
Why does growing old make you more susceptible to cancer?
Older people have accumulated more mutations/DNA damage.
Increased methylation of genes, which turns them OFF.
Weaker immune responses overall.
Why does having chronic inflammation make you more susceptible to cancer?
During chronic inflammation, we have higher numbers of phagocytes floating around eating cells, but they can also damage other healthy cells while protecting us.
Inflammation also = cell proliferation, increased growth factor, more angiogenesis, increased nutrients and oxygen, increased ability to grow due to tissue remodeling.
When we say someone is predisposed to cancer, what do we mean?
Most common is that they probably have something like BRCA1 and/or BRCA2, which are tumor suppressor genes that greatly increase the risk of contracting breast and/or ovarian cancer.
It also includes more general INHERITED factors, such as:
Inefficient breakdown and disposal of carcinogens
Altered ability for DNA repair
Impaired cell proliferation and differentiation
Which BRCA gene results in higher incidences of breast/ovarian cancer?
BRCA1, which has a 55-65% breast cancer rate, 39% ovarian.
What are some common genetic diseases associated with cancer?
Multiple endocrine neoplasia (MEN)
Familial adenomatous polyposis of the colon
Neurofibromatosis
AKA all of these disease involve either tumor growth (benign initially) or cell growth in general.
How do hormones cause cancer?
Hormones are signals sent to many tissues that promote cell replication. Specifically, the sex organs receive these signals and are signaled to grow, but they can sometimes growth uncontrollably, aka testicular cancer or breast cancer.
It is significant because some cancer treatments involve starving cancer cells of hormones by inhibiting that hormone’s production.
How exactly does ionizing radiation increase cancer risk?
It directly kills cells and causes reactive oxygen molecules that interrupt cell membranes and allow radiation to damage cell DNA.
Risk varies with intensity of radiation, duration & number of exposures, area of exposure, age of exposure, AKA if you get a lot of radiation.
What is UV radiation most commonly associated with? Why?
Skin cancer.
UV radiation does not penetrate deep into skin.
Having more of this can help prevent skin cancer.
Melanin
What are some of the most common chemical agents that cause cancer?
Tobacco
Alcohol
Diet (Benzene, Polycyclic aromatic hydrocarbons (PAHS), and high-fat diets)
What are the two types of chemical agents?
Direct and indirect.
Indirect means it becomes metabolized by the body into a direct carcinogen.
How does alcohol affect cancer susceptibility?
Modifies our ability to metabolize carcinogens in the liver and esophagus.
It also has toxic metabolites itself that can lead to DNA mutations.
How much of all cancer deaths is tobacco linked to in the US?
30%!!!!!!!!!!!!!!!
What are benzenes often found in? What about PAHs?
Benzenes are often found in preservatives in foods and drinks.
PAHs, or polycyclic aromatic hydrocarbons, are found in food fried in the oil that has been reused multiple times or smoked/broiled meats.
Name some viruses associated with cancers.
Human papillomavirus (HPV): Cervical, Anogential, oropharyngeal
Hep B & C (HBV, HCV): Hepatocellular carcinoma
Epstein-Barr Virus (EBV): Lymphoma, Nasopharyngeal cancer
Human Herpesvirus-8 (HHV-8): Kaposi’s sarcoma
HTLV-1: T-cell leukemia
Name some bacteria associated with cancers.
Schistosomiasis - bladder
Heliobacter pylori - gastric
How often are viruses implicated in cancers?
15%!!!!!
What are some key differences between a benign neoplasia and a malignant neoplasia?
Benign is well-differentiated (aka it resembles the tissue it originated from). Also localized.
Benign grow slow, usually cause compression rather than invasion, do not spread.
Usually has defined margins, unlike a malignant neoplasia.
If I was looking at some tissues under a microscope, what are some key features I look for to determine if it is benign or malignant neoplastic tissue?
The edges and the shape of the cells. Benign will look more rounded, well-defined.
Malignant will look jagged, out of place, disorganized, and spreading.
See slide 48 for a visual.
What kind of cancer starts out disseminated?
Hematologic cancers.
What is anaplasia? What does high degree of anaplasia imply?
Loss of cell differentiation and cell function.
Higher degree = more aggressive neoplasm.
A less differentiated cell = more like to replicate, more likely to be cancerous.
If I have a malignant neoplasm under my microscope, name some more key features that make it cancer rather than a benign tumor.
Large, variable sized nuclei, usually much bigger than the cytoplasm. (This is because it is actively replicating)
Loss of normal cell features, disorganized appearance.
LACK OF COHESIVE AND ADHESIVE characteristics. AKA it falls apart easily, so it can spread easily.
Increased energy expenditure (aka high metabolic activity)
What are the 4 grades of tissue anaplasia? What is the degree I hope my neoplasm is?
Grade 1-4. Grade 1 means well-differentiated, which is ideal.
Grade 4 is poor differentiation, aka what we DONT want.
What are the environmental factors that cause cancer?
Ionizing radiation
UV radiation
Chemical agents
Viruses and bacteria
How do I name a benign tumor?
Cell type + oma
Examples:
Adenoma: tumor from glandular origins (Adeno means gland)
Papilloma: tumor with fingerlike projections
Epithelioma: tumor with epithelial origins
How do I name a malignant tumor?
cell type + origin tissue type + oma
origin tissue type refers to carcin and sarc.
carcin: malignant epithelial cell
sarc: malignant connective tissue cell.
Adenocarcinoma
Chondrosarcoma
What are some exceptions to malignant tumor naming?
Lymphoma
Leukemia
What are the 3 types of plasia?
Hyperplasia
Metaplasia
Dysplasia
What is hyperplasia?
It simply means an increased number of cells in a given area.
The cells appear normal still, and it could just be physiologic, not always cancer.
REVERSIBLE
What is metaplasia?
Replacement of a differentiated cell type by another differentiated cell type.
Could still be physiologic, not always cancer.
Example: Cervix goes from glandular epithelium to squamous epithelium.
Esophagus goes from squamous to columnar.
REVERSIBLE
What is dysplasia?
Increasing degree of disorganized cell growth or maturation
Often considered a precursor to cancer
Only sometimes reversible.
What types of plasia are reversible?
All of them, but dysplasia is not always reversible.
What is carcinoma-in-situ?
A carcinoma confined to an epithelium.
HAS NOT penetrated basement membrane.
As a result, the prognosis is often better than invasive carcinomas.
What is invasive carcinoma?
Carcinoma that has broken past the basement membrane and can now spread to other tissues.
What is the transition that causes a carcinoma-in-situ to become invasive?
EMT
Epithelial-mesenchymal-transition, aka breaking past the basement membrane.
What are some ways cancer spreads?
Direct extension
Seeding
Metastasis
Define direct extension of cancer.
Localized growth of a cancer, usually breaking through basement membranes and secreting enzymes to spread further.
Define seeding for cancers.
It is a type of direct extension, but involves cancer cells shedding themselves into a body cavity or along some tract in the body.
Most often see in the peritoneal cavity
Define metastasis.
Development of a secondary neoplasm distant from the primary neoplasm.
What kind of spread is most typical of carcinomas? Sarcomas?
Lymphatic spread is more common for carcinomas.
Hematologic spread is more common for sarcomas.
Sarcomas = connective tissue, which is often vascularized and therefore nearby a blood vessel.
Carcinoma is epithelium, which can be either but usually lymph.
What is the TNM classification system in general?
Classifying the primary tumor itself (T)
Classifying if it has spread to regional lymph nodes (N)
Classifying if it has metastasized and how much (M)
What are some common local manifestations of cancer?
Loss of normal parenchymal tissue.
Interruption of tissue integrity, which commonly leads to ulcerations, bleeding, necrosis, impaired wound healing.
Compression of local structures.
Local palpable mass or asymmetrical enlargement.
What are some more systemic manifestations of cancer?
Pain (due to compression or destruction)
Fever (due to release of pyrogens)
Pruritis (cytokines?)
Jaundice (excess bilirubin)
Infection (impaired immune function)
Pathologic fractures (extremely weakened bone breaks under low stress)
How does cancer cause pain?
Compression, infiltration, and invasion of local tissue
Metastatic cancers cause the most pain usually.
Often the most painful cancers are bone, testicular, and muscular.
An organ will cause more diffuse and referred pain.
How does cancer cause fever?
Releasing pyrogens from cancer cells, along with cytokines.
Cancers often associated with fever are lymphoma and leukemia.
up to 7-25% of unknown fever origins are cancer ):
How does cancer theoretically cause pruritis?
Cytokines and/or cholestasis.
Associated most often with leukemia, lymphoma, and liver cancer or any cancer causing bile duct obstruction/cholestasis.
Note: Bile salts build up, which cause cause peripheral nerve fiber irritation.
What is jaundice? How does cancer cause it?
Jaundice is excess bilirubin, which appears physically as a yellowing of the skin, eyes, and mucous membranes.
Associated with cancers that cause bile duct obstruction, such as liver, gallbladder, bile duct, and pancreatic cancer, along with metastatic cancers.
What cancers tend to affect the immune system directly?
Leukemia, Myeloma, Lymphoma, aka any cancer related to bone marrow/lymph.
How does cancer cause pathologic fractures? What is often a warning of it?
Invasive cancers or bone-related cancers cause weakened bone matrix, so it breaks easily. Cancer can also leech off the calcium, so people will often have hypercalcemia!!!
Bones are also just common places for cancers to metastasize to.
What are the 4 hematologic manifestations of cancer?
Hemorrhage
Anemia
Leukocytosis
Leukopenia
What kind of cancers usually cause hemorrhages?
Lung, GI, and GU, because they are near highly vascularized tissues and are tracts.
What kind of cancers usually cause anemia?
Cancers that cause blood loss.
Cancers affecting bone marrow, which directly impacts RBC production. (Lymphoma, myeloma, leukemia)
Metastases to bone marrow, creating the same effect as above.
What kind of cancers usually cause leukocytosis?
Leukemia, which often results in immature and dysfuctional WBCs. Also seen in thymoma.
AML, CML, CLL
Acute myeloid leukemia
Chronic myeloid leukemia
Chronic lymphocytic leukemia
What kind of cancers usually cause leukopenia?
Lymphoma, myeloma, leukemia, and bone marrow metastases.
They take up space in the bone, squishing the bone marrow.
Acute myelomonocytic leukemia
Monocytic leukemia
AKA leukemias that kill monocytes
What is cachexia-anorexia syndrome? What kind of cancers typically cause it?
Weight loss, wasting of body fat & muscle, loss of appetite, and weakness.
Commonly seen in people with solid tumors and upper GI/pancreatic tumors.
What causes the anorexic state in cachexia-anorexia?
Suppression of satiety in the hypothalamus, often by TNF-alpha, IL-1, and IL-6 due to tumor releasing inflammatory mediators.
What causes the cachexic state in cachexia-anorexia?
Suppression of lipoprotein lipase which releases fatty acids into tissues to anabolic/catabolic reactions.
Cancer lesions often steal nutrients.
Abnormal metabolism of amino acids also leads to an increased depletion of muscles.
They also may have IMPAIRED nutrient absorption.
AKA cancer steals nutrients and people with cancer can’t metabolize nutrients well in general.
What is paraneoplastic syndrome?
Manifestations of cancer in sites/areas that are NOT directly affected by the disease.
What are some causes of paraneoplastic syndrome?
Secretion of hormones
Cytokines and inflammatory response
Most common in lymphoma or lung/breast/ovarian cancer.
Varies widely depending on the cancer.
What is one of the most common symptoms of paraneoplastic syndrome?
Hypercalcemia, usually caused by an excess production of PTH
(Parathyroid hormone)
10-20% of all cancer patients.
What are some other common manifestations of cancer?
General: Fever, night sweats, anorexia-cachexia
Dermatologic: Itching, flushing, pigmented skin lesions, herpes zoster.
GI: watery diarrhea
Endocrine: Cushing’s, abnormal glucose metabolism, SIADH
Hematologic: thrombocytopenia, pro-coagulant status, anemia
Renal: Glomerulonephritis, impaired renal function
Neurologic: Neuropathy, weakness, myasthenia gravis
Note: SIADH stands for syndrome of inappropriate secretion of anti-diuretic hormone
Pro-coagulant status is usually due to increased platelet count, which is a result of inflammation.
What causes almost half of all deaths when a patient has cancer?
Infections, such as pneumonia, or peritonitis, or sepsis.
What causes almost a quarter of all deaths when a patient has cancer?
Organ insufficiency/failure
What are the 5 causes of death in cancer patients?
Metastases = poor prognoses.
Infection
Organ insufficiency/failure
Infarction of major organs
Hemorrhage
