Cancer

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-oma

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benign tumor

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malignancies (cancers)

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invasive, metastatic

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hamartomas

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overgrowths

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neoplasms

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new growths

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carcinoma

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a malignant epithelial cancer

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sarcoma

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a malignant connective tissue cancer

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leukemia

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a malignant blood cancer

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lymphoma

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a malignant lymphatic cancer

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exceptions to oma rule

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blastoma (blast cells), glioma (glial cells of the brain), lymphoma (lymphoid cells), melanoma (melanocytes), mesothelioma (mesothelium lining of abdonimal, pleural, and pericardial cavities), seminoma (testicular)

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choristoma

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non-neoplastic. Tissue that is out of place

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angio-

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blood vessel or lymphatics

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chondro-

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cartilage

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fibro-

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fibroblasts

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leiomyo-

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smooth muscle

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lip-

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fat

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osteo-

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bone

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rhabdomyo-

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skeletal muscle

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benign tumors

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smooth, well-circumscribed border, non-metastatic, low nuclear-to-cytoplasm ratio, small regular nuclei, not mitotically active, no necrosis,

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malignant tumors

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infiltrative, pleomorphic nuclei, prominent and irregular nucleoli, high N:C ratio, mitotically active with abnormal mitotic figures, areas of necrosis (due to lack of blood supply), metastatic

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adeno-

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glandular epithelial cancer

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Chronic myelogenous leukemia

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chronic myeloproliferative disorder, due to balanced translocation of chromosomes 9:22, characterized by BCR-ABL fusion, leading to over-expression of ABL, targeted by imatinib

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nib (ending of a drug, therapy)

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tyrosine kinase inhibitor

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primary tumors spread three ways

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1) hematogenous, 2) lymphatic, 3) transcoelomic (pericardial, peritoneal, and pleural cavities)

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cachexia

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wasting, causation of many cancer types. Mechanism is tumor necrosis factor (TNF-alpha)

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hypercalcemia

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squamous cell lung cancers. Parathyroid hormone-like products

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polycythemia

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High hemoglobin. Hepatocellular carcinoma, renal cell carcinoma, erythopoietin mechanism

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carcinogenesis

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"the process by which cells acquire attributes that confer a malignant phenotype." applies to all cancers, not only carcinomas

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oncogene

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normal genes that, when mutated or otherwise altered to a more active form, or over-expressed, contribute toward a neoplastic phenotype...normal form of an oncogene is a proto-oncogene. KRAS, HER2 are examples

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tumor supressor gene

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suppresses cancer when normally active. When absent or mutated and not functioning properly, cancer occurs. RB and P53 (TP53) are examples

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Six hallmarks of cancer

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1) resisting cell death, 2) sustaining proliferative signaling, 3) evading growth suppressors, 4) inducing angiogenesis, 5) enabling replicative immortality, 6) activating invasion and metastasis

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resisting cell death

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avoidance of apoptosis. Particularly intrinsic pathway bc BCL2 gene overexpressed. BCL2 = oncogene

BCL2 inhibits sensors and effectors from binding to the mitochondrion. Therefore, mitochondria will not release cytochrome C and trigger a caspase response.

translocation of chromosomes 14;18 result in BCL2 overexpression

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overexpression of cell signaling

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TKIs over-expressed stimulates proliferation of cells. increased autocrine signaling encouraging cell growth and division (HER 2)

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trastuzumab (herceptin)

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targeted therapy for HER2 expression in breast cancer.

drugs ending in -mab signify monoclonal antibodies

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cancers escape growth controls

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RB, E2F

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growth of own blood supply

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recruiting of blood to nourish tumor. Otherwise, necrosis may occur. VEGF most prominent signaling molecule of blood vessel growth

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Cancer cells divide without end

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increased telomerase activity allows them to avoid senesence (programmed cell death)

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metastasis

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cancer cells have ability to spread and invade. Use vessels (blood and lymphatic) to move long distances.

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altered metabolism

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an emerging hallmark where some cancer cells have found ways to efficiently provide energy via only glycolysis. Even in the presence or absence of oxygen. these cells don't utilize oxidative phosphorylation, which we do for increased efficiency.

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escaping detection

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an emerging hallmark where some cancer cells can turn off antigen expression and secrete antiproliferative factors. They do this in order to avoid immune cells (like lymphocytes) that would destroy them

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inflammatory cells

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an enabling characteristic of cancer. Angiogenic factors and growth factors involved in response to inflammation.

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Familial Adenomatous Polyposis (FAP)

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autosomal dominant, colon carpeted with polyps, result of tumor suppressor missense mutation and deletion

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microsatellite instability

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contributes to cancer...defective mismatch repair mutations leave altered DNA abnormal. Mutator phenotype expressed.

Can also have epigenetic changes due to hypermethylation

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Hereditary non-polyposis colon cancer (HNPCC; Lynch Syndrome)

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due to germline mutations in mismatch repair genes. 3% of colorectal cancers, autosomal dominant, MLH1, MSH2, MSH6, PMS2

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MicroRNAs

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regulate gene expression via down regulation that masks coding regions, effectively making them noncoding. Tissue specific expression.

Mature microRNAs suppress translation by inserting a dicer in front of the ribosome, blocking further ribosome movement.

Can be oncogenes (promoter demethylation) or tumor suppressors (deletions of transcription factors/promoters, promoter methylation)

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aflatoxin

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hepatocellular carcinoma, reactivates metabolite causing DNA damage

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asbestos

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mesothelioma, unknown mechanism

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cigarette smoke

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lung cancer, reactive metabolite causing DNA damage

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radiation

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leukemia, thyroid cancer, mutations and genome-level breakage

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sunlight

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carcinoma, melanoma, pyrimidine dimers

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Human Herpes Virus 8

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body cavity lymphoma, kaposi sarcoma

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Epstein-Barr virus

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Burkitt lymphoma

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Human papilloma virus

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cervical carcinoma

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hepatitis B virus

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hepatocellular carcinoma

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Cancer Etiology

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It is important to note that it is difficult to pinpoint the exact cause of cancer or the moment it occurred. Cancer takes years to develop, so not exact as to when initiation event happened.

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Cancer Cell Characteristics (excluding 6 hallmarks)

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derived from normal cells, clonal or multi-clonal, homogenous and heterogenous, 50-150 mutations found, but only 5-15 are the drivers that lead to transformation from normal cell to cancer cell.

six hallmarks:
avoid apoptosis, angiogenesis, hyperproliferation of growth factors, immortal (avoid senescence w/ increased telomerase activity), metastasize, avoid tumor suppressors

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Log-Kill Hypothesis

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Since a tumor is millions of cells, each round of chemotherapy or drug administration can only kill a fraction of the cells (as there are too many to eliminate in one therapy). So rounds of chemo must be administered, with each round decreasing the cancer cells on a logarithmic scale. Additionally, because cancer cells not killed will continue to divide, it is important to be aggressive in chemo, as one cell will proliferate into a whole new tumor. Therefore, it is hard to ensure all of the cancer is ever gone, and it is common for a patient to get cancer again years down the road.

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Chemotherapy Resistance

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contributes to over 50% of failures in chemo. Could be single agent or multi-agent. Many potential mechanisms (increased eflux of drug out of cell, decreased influx of drug into cell or nucleus, etc), but all of them have one main hallmark: they allow the cancer cells to combat the effects on the drug and avoid therapy.

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Combination Chemotherapy

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A way to resist cancer cell resistance to chemo, multiple agents used in rounds or at once to aggressively destroy cancer. Drugs can often have a cycled administration due to harmful side effects. If cyclical, it will occur every month bc that is when the worst side effects of a specific drug are gone.

Examples of why combination therapy used: single therapy ineffective, different mechanisms of action to avoid resistance, different mechanisms of resistance.

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Systemic Toxicity of Chemo

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there are many direct and indirect toxicities of chemotherapy. It will often cause extreme discomfort, loss of hair, nausea, bone marrow problems, loss of fertility, etc. Also can lead to secondary malignancies.

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Cell-Cycle Specific Drugs

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targeted for dividing cells; cancer cells are dividing more frequently, therefore this is a good way to attack them.

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Antimetabolites

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prevent the synthesis of DNA/RNA. Therefore, synthesis phase cannot occur. Thiopurines prevent the synthesis of purines. Fluorouracil (5-FU) blocks thymidylate synthase, so no thymines can be created. Dihydrofolate Reducatse, blocks protein and DNA/RNA synthesis. All of these prevent synthesis of new DNA. Cell Cycle Specific

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Vinca Alkaloids

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Bind tubulin and prevent mitotic spindle formation (metaphase arrest). Cell Cycle Specific.

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Taxoids

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induce the polymerization/stabilization of microtubules. To the point where they cannot depolymerize; this means they prevent the movement into anaphase by arresting chromosomes at metaphase plate. Cell Cycle Specific

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epipodophyllotoxins

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inihibit topoisomerase II leading to large breaks of dsDNA. These frequent breaks cause errors during replication and eventually apoptosis. Cell Cycle Specific

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Cell Cycle Nonspecific Drugs

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can work outside of the cell cycle (but also can work in the cell cycle)

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alkylating agents

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Irreversible changes in DNA induced by cross-linking of two chlorines; can be intra and inter strand. Changes RNA and proteins as well. Non Cell Cycle Specific

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antibiotics

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intercalates in DNA and inhibits transcription so cell cannot create proteins. Also inhibits replication so cell cycle stops. Non Cell Cycle Specific

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camptothecins

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inhibits topoisomerase I, leading to single stranded breaks in DNA. Increased probability of mutations and arrest of cell cycle. Inhibits replication and transcription. Non Cell Cycle Specific.

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Platinum Compounds

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intra-/interstrand crosslinks in DNA created. Non Cell Cycle Specific. Cisplatin and Carboplatin.

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Sex Hormone Targeting

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Non Cell Cycle Specific. Competitive binding to nuclear hormone receptors. Targeted antagonists or agonists (or selective receptor modulators). Tamoxifen (breast), Flutamide (prostate), Fulvestrant (breast), Letrozole (breast).

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Agonists

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activate hormone receptor

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Antagonists

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deactivate hormone receptor. Therefore the hormone cannot bind. Useful in sex hormone specific cancers (prostate and breast) as they will prevent androgens and estrogens from binding.

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Retinoic Acid Receptor

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Non-continuous therapy due to slow growing stem cell process. Most patients not resistant (nor do they acquire resistance) to the treatment.

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Breast Cancer Classification

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5% Genetic (BRCA1, BRCA2) mutations acquired from parent
70% spontaneous mutations (not inherited)
20% HER2/Neu-positive
10% triple negative

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EGFR

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oncogenic activity in many tumors. Kinase inhibitors and antibodies utilized as targeting agents.

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Angiogenesis inhibitors

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Bevacizumab (Avastin) a VEGF antibody (prevents VEGF expression)

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Vemurafenib (Zelboraf)

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involved in downstream RAF mutations, particularly useful for melanoma therapy.

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Proteasome Inhibitors

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Bortezomib (Velcade) inhibits active site of 26S proteasome

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Epigenetics and Cancer

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Cancer cells have some sort of change in gene expression compared to normal cells. This can be actual mutations changing DNA sequences. Or epigenetic modifications, which silence areas of the genome without changing their sequence. Silencing a tumor suppressor is an epigenetic change. Hypomethylating an oncogene is an epigenetic change.

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Genomic Imprinting

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expression of a gene in a parent-of-origin-specific location. Only happens in a handful of genes, but critical to our development.

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DNA methylation

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silences a gene w/o changing the sequence. Must be demethylated to be transcribed, as methylated DNA cannot bind transcription factors. Methyl transferase proteins involved in this process. Dangerous when methylated CpG dinucleotides undergo a mutation, bc they will not be corrected.

Hypomethylation of genome leads to chromosomal rearrangements, activation of retrotransposons, and activation of growth promoter genes.

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DNA Demethylating Agents

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Incorporated into DNA; direct and irreversible inhibition of DNA methyltransferase. Reactivation of tumor suppressor genes by demethylating them.

Azacitidine (Vidaza)

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Histone Deacetylase Inhibitors

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Vorinostat (SAHA). By preventing the deacetylation of histones, genes are transcribed and cannot be turned off. This is useful in tumor suppressor instances, where epigenetic modifications of cancers would like to deacetylate and methylate (silence) a histone incorporated with a particular gene.

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Immunotherapy

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Inducing, enhancing, or suppressing an immune response. Immune cells kill tumor cells through specific tumor antigens, immune cells affect cancer growth and metastasis, can ameliorate negative side effects of chemo.

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Gene Therapy

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Genetic sequence must be transported to cell, bind to cell surface receptor, imported into the cell and uncoated, taken to nuclear lamina, imported into nucleus, incorporate into DNA, desired transcript final product.

Specificity of target cells is a persistent problem, as well as ongoing expression.