Cancer- Midterm (ALL terms + definitions)

All terms + Definitions

Homeotic Genes

a group of genes that control the pattern of body formation during early embryonic development. These encode transcription factors that direct cells to form various parts of the body.

How do homeobox genes relate to homeotic genes?

They are at of one another and are both present in plants/animals.

Homeobox

180 bp long DNA segment present Homeobox genes.

Homeodomain

60 AA protein domain encoded by the homeobox region

How do homeodomains bind DNA

The second and third helices form a helix-turn-helix structure

Hox Genes

These are a type of homeobox genes (which are a type of homeotic gene) and these were discovered in the fruit fly and present in all bilaterian animals.

Purpose: set up the correct positioning of body parts in an organism along the anterior-posterior axis.

Why are hox genes important?

They have spatial and temporal collinearity in expression over AP axis. ex: 3’ genes are expressed more anterior and earlier and 5’ genes are expressed more posterior and later..

What happens if hox genes are not present

No lumbar vertebrate is formed/ribs project from the posterior vertebrae

ex: Synpolydactyly Type II, characterized by distal limb malformations where 2 digits are fused together.

HOXB13 development

Development and maintenance of skin, required for normal differentiation/secretory function of prostate gland.

HoxB13 in cancer

-mediates tamoxifen resistance and invasiveness in human breast cancer

-promotes cell proliferation + tumor growth in ovarian cancer.

Wnt Signaling Pathway

Plays important roles in embryonic development. Stem cell fate determination/adult tissue self renewal. Proliferation of crypt progenitor cells in the intestinal epithelium and terminal differentiation of Paneth cells. Required for hair follicle establishment. Induces osteogenic differentiation.

How is the Wnt pathway altered in cancer

-important role during development

-should be consequently downregulated in differentiated cells

-abnormal activation of the Wnt/b-catenin pathway that has been reported as one of the predisposing factors in many cancers.

What can increase the b-catenin levels?

1. mutations in that gene

2. abnormalities in the b-catenin destruction complex

3. mutations in APC

4. overexpression of Wnt ligands

5. Loss of Wnt pathway inhibitors or decreased activity of regulatory pathways

Walk me through the Hedgehog Pathway

This starts with a SHH ligand binding to the receptor and this triggeres Gli proteins to move into the cell nucleus and turns genes off/on to guide cellular growth

What are common themes shared between development and cancer

development requires precise spatail/temporal expression of several genes and activation of signaling pathways. many genes/pathways play an important role in development implicated in cancer. reactivation of developmental pathways in adults can occur as a result of mutations or epigenetic remodeling.

Benign tumors

not cancerous, can be removed (don’t come back) cells in benign tumors do not spread to other parts of the body.

Malignant Tumors

cancerous. these invade nearby tissues and spread to other parts of the body. The spread is metastasis

Hematoxylin

nuclei blue

Eosin

cytoplasm/ECM pink

Histological Features of Cancer Cells

-loss of differentiation

-differences in cell arangmenet (multi-layered epithelium)

-cell shape + nucleus-cytoplasm ratio changes

-morphology of the nucleus and/or chromatin changes

-increase in frequency of mitotic cells

-tumor grade depends on extent of differences from normal

Differences in Structure between a cancer cell and a normal cell

Chemical Carcinogenesis Theory

Chimney sweepers had large exposure to coal and were exposed to polycylic aromatic hydrocarbons in the soot. Chemical carcinogenesis was established from this

Epstein-Barr Virus

First identified human tumor virus. Large DNA virus that causes solid tumors/lymphoid malignancies.

HPV vs. HCV

HPV has a small DNA genoma and HCV is a ss-RNA virus that both infects hepatocytes and causes chronic liver inflammation.

HTLV-1

oncogenic retrovirus that infects T cells and can cause adult T cell lymphoma

Somatic Mutation of Cancer Theory

Cancer is largely the result of acquired genetic + epigenetic changes.

Proto-oncogenes

Genes whose aberrant activation of oncogenes drive tumor progression

Tumor Suppressors

genes who loss of function promotes tumor progression

What is the most important risk factor for cancer?

AGE because mutations and genomic alterations accumulate, DNA repair/genome maintenance is less effective and cells have more stressors, immune surveillenc is less effective and this changes in ways that can promote tumor development.

How many cells does our body have

3.7 × 10^13

Why do normal cells become cancer cells?

they die and are constantly replaced during our lifetime and the genetic material then needs to be copied which increases the potential chance of error.

What is the lifetime risk of cancer correlated with?

Total # of divisions of the normal self-renewing cells, maintaining that tissues homeostasis.

Cancer causing mutations can be:

inherited (small percentage of cancers) or introduced during somatic cell division

What are the two types of cancers?

Epithelia nd non-epithelial

Epithelial Cancer: Carcinoma

most common cancer. these are tumors arising from the epithelial cells (skin/cells that line internal organs and glands)

Epithelial Cancer: Carcinoma: Adenocarcinoma

Refers to cancer that arises in secretary epithelial cells of glands

ex: breast, prostate, ovarian, and colon

Non-Epithelial: Sarcoma

cancer that arises from connective tissues

Non-Epithelial: Hematopoetic Cancer

cancers in blood forming cells/cells of the immune system

-leukemia and lymphoma

Leukemia

cancer of the blood cells that moves freely through the circulation but in rare cases, RBC - they are liquid tumors

Lymphoma

tumors of the lymphoid lineage that aggregates to form solid tumor masses and found in the lymph notes.

Non-epithelial cancer: Neuroectodermal

Arise from cells that form the various components of central and peripheral NS

What are some things that could confer new attributes to cells and contribute to the evolution of a malignant phenotype

UV light exposure, ionizing radiation, chemical exposure, replication errors, cellular metabolism, apoptosis

What is the difference between Hereditary vs. Sporadic cancers

both involve genetic changes, hereditary (risk transmitted through germline) and sporadic cancers are not transmitted to offspring

oncogene

mutations are dominant acting, promotes cancer, usually by cell division stimulation

proto-oncogenes

responsible for basic cellular functions in normal cells; when mutated, becomes oncogenes.

Discovery of cancer-causing rous sarcoma virus

-the carcinogenic agent is a virus that could pass through a fine filter.

-the virus is capable of multiplying within the chicken tissue (more virus can be recovered that way) from the infected tumor tissue than was originally infected)

How did RSV chicken fibroblast cells show traits of cancer?

They became transformed which means that it was converted from a normal cell to a tumor cell.

What are the 8 Properties of transformed cells?

altered morphology rit

loss of contact inhibition

ability to grow without attachment

ability to proliferate indefinitely

high saturation density

reduced requirement of exogenous mitogenic growth factors

increased glucose transport

tumorigenicity in a permissive host

alaah rit

Is RSV required to maintain transformed phenotype or is the initial infection sufficient?

There are temp-sensitive RSV mutants. The viral transforming gene is required to initiate and maintain transformed phenotype.

How does RSV transmit its genome over many generations?

DNA gets integrated into the host cells chromosomes. RSV genome is made of ss-rna that cannot be integrated directly into the host DNA.

Does the RSV Genome have a “cellular transformation element?”

-it has a relatively small genome (9 kB) and should only have a few genes

-has at least 3 genes necessary for virus replication

-potentially contains one gene that is responsible for transformation - src “sarcoma’

src

sarcoma

How did they discover the transforming element in RSV

• WT RSV RNA has all sequences

• Make radioactive cDNA probes using reverse transcriptase

• hybridize probes to transform defective mutant RSV RNA

• discarded RNA: DNA hybrids that are formed

• isolated probes that did not hybridize

• use to follow the fate of src after infecting chicken cells with rsv

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Discovery of the “src” oncogene

-it is present in chicken cells that are infected with RSV

-it is present in the DNA of uninfected chicken cells

-src sequences are found in and from all bvertebrate

what is the avian leukosis virus (ALV)

RSV genome is closely related to that of a relatively common infectious agent in a chicken. The src gene is present in RSV and absent in its retroviral ancestral ALV

how does src drive tumor progression

c-src is a non-receptor protein kinase

what are the three types of protein kinases?

1. Serine-protein kinase

2. tyrosine protein kinase (RTK and nRTK)

3. dual specificity protein kinase

how to discover non viral oncogenes?

How do oncogenes become activated in cancer?

1. Activating mutations

2. Gene Amplification

3. Chromosomal Translocation

Describe gene amplification in oncogenic activation

-copy number increase of a restricted region of a chromosome arm, it is prevalent in some tumors and associated with overexpression of the amplified genes, results in increased expression of oncogenes in many cases.

what is myc amplification

this is very frequent in human cancers. a genetic alteration where extra copies of the MYC gene are created, leading to high protein levels that drive aggressive cancer cell growth.

What is chromosomal translocation?

Present with ABL activation in chromic myeloid leukemia and this results in the formation of a new formation gene called BCR-ABL that is constitutively active.

What are 3 other mechanisms by which oncogenes are activated in the cell?

• activating mutations

• amplifcations of genomic region harboring the oncogene

• chromosomal translocation

• increase oncorportein stability

• increased oncoprotein expression

• upregulation of upstream activating pathways

Theory of Oncogene Addiction

a hyperactive oncogene takes over the cellular machinery. Because this driver is so powerful, the cancer cell adapts by shutting down or completely losing alternative, redundant survival pathway to save energy

inhibition of this specific oncogene is suffiicent to halt the neoplastic phenotype

Imatinib

This is a drug that targets the BCR-ABL fusion protein in CML, implying that leukemia cells are addicted to the ABL oncogene. Stronger evidence comes from imatinib’s effectiveness in targeting c-kit oncogene in gastrointestinal stromal tumors.

-unlike CML, gastrointestinal stromal tumors is a cancer with many genetic abnormalities.

oncogenic shock theory

different rates of decay of proliferative and death signal emanating from the same oncogene

what is the limitation in exploiting oncogenic addiction

clinically - no pt with a metastatic epithelial tumor is cured with just one drug.

the two theories to help explain this is oncogenic escape and tumor heterogeneity

tumor suppressor genes

genes whose normal (WT) products prevent uncontrolled cell proliferation to promote the elimination/repair of damages cells, thereby protecting against cancer.

what is the somatic cell hybdridization experiement

-henry harris and colleagues fused normal and tumor cells

-the resulting hybrids contained chromosomes from both parental cells

-the hybrid cells were not capable of forming tumors

-genes from a normal cell suppressed tumor development.

retinoblastoma

ped cancer. the retinoblasts (which should normally develop into retinal photoreceptors/nerve cells) fail and mato differentiate and continue to divide which forms tumors. this may be hereditary or sporatic and can either be unilateral or bilaterial

what is alfred knudsen’s statistical study of retinoblastoma?

he analyzed 48 retinoblastoma patients and noticed that if it affects both eyes, it is diagnosed earlier as opposed to one eye being diagnosed later. This is more frequent in patients with hereditary disease.

Knudson’s “Two Hit” hypothesis for retinoblastoma

there must be a TSG whose WT function prevents retinal cells from becoming cancerous. Through careful cytogenetic analysis, the gene responsibel for retinoblastoma Rb1

How does the cell lose the second Rb allele?

inactivating mutations

-the probability of inactivating a single gene copy by mutation is 10^-6 per cell generation

the probablility of silencing both copies is 10 ^ -12 per cell generation

how does Rb protects us from cancer?

G1 checkpoint also known as restriction point

-once a cell croses