Cell Biology Ch 19

What is cancer?

Cancer results from a breakdown of the regulatory mechanisms that govern normal cell behavior.

How do cancer cells grow and divide?

in an uncontrolled manner

What is a tumor?

any abnormal proliferation of cells

What are benign tumors?

remain confined to the original location, neither invading surrounding normal tissue nor spreading to distant body sites

What are malignant tumors?

can invade surrounding normal tissue and spread throughout the body via the circulatory or lymphatic systems (metastasis)

What kind of tumors can be properly referred to as cancers?

malignant

What is the difference between malignant and benign tumors?

Benign tumors:

- Well-differentiated

- Encapsulated

-don't metastasize

Malignant tumors:

- Disorganized

- Cells less-differentiated

- May spread

As a tumor grows, what does it need?

increased vascularization (blood supply) to provide oxygen and nutrients to the rapidly dividing cells

What are the three main groups of cancers?

- carcinomas

- sarcomas

- leukemias and lymphomas

What are carcinomas?

malignancies of epithelial cells (about 90% of human cancers)

What are sarcomas?

solid tumors of connective tissue such as muscle, bone, cartilage, and fibrous tissue (rare in humans)

What are leukemias and lymphomas?

arise from the blood-forming cells and immune system cells, respectively

How are tumors classified?

according to tissue of origin and type of cell involved

What are the four most common cancers?

prostate, breast, lung, and colon/rectum

What is one of the biggest risk factors for cancer?

increasing age

At the cellular level, development of cancer is a multistep process. Briefly describe this process.

Mutation and selection for cells with progressively increasing capacity for proliferation, survival, invasion, and metastasis

Describe tumor initiation in regards to cancer development.

mutation leads to abnormal proliferation of a single cell, which grows into a population of clonal tumor cells

Describe tumor progression in regards to cancer development.

additional mutations occur within cells of the tumor population

- where more rounds of clonal selection occurs

What is clonal selection?

The selective mutations that confer tumor forming abnormalities pass to the decedent cells

A proliferative cell population can give rise to what?

a small benign neoplasm (or adenoma) with further rounds of clonal selection leading to malignant carcinomas

Cancer cells have characteristic properties that distinguish them from normal cells and contribute to malignancy. What are some?

1. Uncontrolled proliferation

2. Reduced dependence on growth factors

3. Reduced cell adhesion molecules

4. Secretion of proteases

5. Promotion of angiogenesis

6. Abnormal differentiation

7. Failure to undergo apoptosis

8. Capacity for unlimited replication

Describe proliferation in normal cells.

they display density-dependent inhibition, in which they proliferate until reaching a finite cell density, determined partly by the availability of growth factors. They then cease proliferating and are arrested in the G0 stage of the cell cycle or become quiescent

Describe proliferation in cancer cells.

- cells are not restricted by growth factor availability or

cell-cell contact.

- They don't respond to the signals that cause normal cells to cease proliferation but grow to high densities in culture.

Describe cancer cells in relation to growth factors.

Some cancer cells produce growth factors that stimulate their own proliferation (autocrine growth stimulation)

True or false: Many cancer cells can grow in the absence of growth factors required by normal cells.

true

What is an example of growth factor dependence in cancer cells?

unregulated activity of growth factor receptors or other proteins (e.g., Ras proteins or protein kinases)

True or false: Cancer cells are less regulated by cell-cell and cell-matrix interactions.

true

Why are cancer cells less adhesive than normal cells?

due to reduced expression of cell surface adhesion molecules

Loss of ________ is important in development of carcinomas (epithelial

cancers).

E-cadherin

What do cancer cells secrete?

proteases

What are proteases?

digest extracellular matrix components, allowing them to invade adjacent normal tissues

What is the result of cancer cells secreting growth factors?

(VEGF) that promote formation of new blood vessels

(angiogenesis)

True or false: Many cancer cells fail to undergo programmed cell death or apoptosis and have longer life spans than normal cells.

true

How much telomeres do normal cells have?

limited amounts of telomerase and gradually lose telomeres, leading to cessation of replication

How much telomeres do cancer cells have? What does this allow for?

high levels of telomerase, allowing them to maintain chromosome ends for an indefinite number of divisions

What are telomeres?

regions at the ends of chromosomes

What is the function of telomeres?

"cap" the ends of the chromosome

What repairs and maintains the length of telomere ends?

telomerase

What is the activity of telomeres in many different kinds of cells?

- active in stem cells

- inactive in most adult cells

- active in cancer cells

What are carcinogens?

substances that cause cancer and can induce DNA damage and mutations

What kind of Radiation and chemical carcinogens can damage DNA and induce mutations?

- Solar ultraviolet radiation

- Chemicals in tobacco smoke include benzo(α)pyrene,

dimethylnitrosamine, and nickel compounds

- Aflatoxin

- Some viruses directly mutate oncogenic genes

What is the main cause of skin cancer?

solar radiation

What is Aflatoxin?

a liver toxin produced by molds that contaminate improperly stored peanuts and grains

What carcinogens are tumor promoters that stimulate cell proliferation?

- Hormones, particularly estrogens

- Asbestos (promotes inflammatory environment)

- Heliobacter pylori causes stomach cancer

viruses account for _______% of cancer world-wide

10-20

Study of tumor induction was advanced by what kind of development?

of in vitro assays to detect cell transformation

What is cell transformation?

conversion of normal cells to tumor cells

What are oncogenes?

specific genes that can induce cell transformation

Why is it important to identify the viral oncogenes capable of inducing cancers?

to better understand the identification of cellular oncogenes, which are involved in the development of non-virus-induced cancers

What are Proto-oncogenes?

normal-cell genes from which oncogenes originate

What was the function of oncogenes?

encode proteins in the signaling pathways that control

normal cell proliferation

- src, ras, raf

Oncogenes are _______ expressed or ______ forms of the proto-oncogenes.

abnormally; mutated

What the first human oncogene identified?

the homolog of the rasH oncogene of Harvey sarcoma virus

What are the three members of the ras gene family most frequently encountered in human tumors?

rasH, rasK, and rasN

How are ras oncogenes made?

they are generated in tumor cells from mutations during tumor development.

How do oncogenes differ from proto-oncogenes?

by point mutations resulting in single amino acid substitutions

What are point mutations from oncogenes caused from?

chemical carcinogens

What do ras genes encode?

guanine-binding proteins that function in transduction of mitogenic signals from many growth factor receptors

What do ras proteins alternate between?

active (GTP-bound) and inactive (GDP-bound) states

How do mutations of ras oncogenes maintain the Ras proteins?

constitutively in the active GTP-bound conformation.

Do Oncogenic Ras proteins respond to GAP?

no

What does Oncogenic Ras proteins not responding to GAP result in?

decreased GTPase activity

GTPases ________ GTP to GDP to _______ g proteins

hydrolyze; inactivate

How does RAS act in its constitutively activate state?

can act as a molecular switch for downstream targets to stimulate proliferation

What kind of abnormalities can convert proto-oncogenes to oncogenes?

translocation of genes, duplications, and deletions

How has novel oncogenes been discovered?

through molecular cloning and analysis of rearranged DNA sequences

What occurs in Burkitt's lymphoma?

chromosome translocation inserts c-myc oncogene into an immunoglobulin locus, where it is expressed in an unregulated manner

What is the function of c-myc?

encodes a transcription factor normally induced in response to growth factor stimulation

What results in the overexpression of c-myc?

can result in cell proliferation and may be associated with

cancer.

What does translocations often result in?

rearrangements of coding sequences and abnormal gene products

What does the translocation of the abl proto-oncogene from chromosome 9 to chromosome 22 in chronic myeloid leukemia result in?

leads to fusion of abl with bcr, and production of a Bcr/Abl fusion protein, further resulting in unregulated activity of Abl tyrosine kinase, leading to cell transformation

What is the result of Oncogenes encoding growth factors, growth factor receptors, and signaling proteins?

stimulate cell proliferation and also prevent cell death

What happens to a normal cell in the absence of Wnt stimulation?

β-catenin is phosphorylated by GSK-3 in a complex with axin, APC, and casein kinase-1 (the destruction complex), leading to β-catenin ubiquitination and degradation

What happens to cells with mutations that prevent degradation of β-catenin in the absence of Wnt signaling?

converts β-catenin to an oncogene

What are the targets of oncogenes in the presence of growth factors?

the proapoptotic Bcl-2 family member Bad and the FOXO transcription factor, which stimulates transcription of another proapoptotic Bcl-2 family member, Bim

What is the result of Phosphorylation by Akt in the presence of growth factors?

inhibits both Bad and FOXO, promoting cell survival

How does Bcl-2 act as an oncogene?

by inhibiting the release of cytochrome c from mitochondria

What is the function of tumor suppressor genes?

normally act to inhibit tumor formation by inhibiting proliferation

Genes derived from one cell, act to ______ the tumor forming properties of the other cells genes

inhibit

What is an example of genes derived from one cell, acting to inhibit the tumor forming properties of the other cells genes?

Rb

What does Inherited retinoblastoma result from?

a defective copy of the Rb gene

Why is Non-inherited retinoblastoma in children rare?

Because its development occurs only if two independent mutations of Rb occur in the same cell

What does Rb mutations in adult cancer mutations mostly result in?

the development of substantial amount of bladder, breast and lung carcinomas

What is the target of human papillomavirus?

Rb proteins

p53 plays a role is about ____% of all cancers

50

What are BRCA1 and BRACA2 the cause of?

the causes for hereditary breast cancer

What is an example of antagonism between oncogene products

and tumor suppressor gene products?

the tumor suppressor gene PTEN

Describe PTEN.

a lipid phosphatase that dephosphorylates PIP3, yielding PIP2, countering the action of the oncogene proteins PI 3-kinase and Akt, which promote cell proliferation and survival.

What do Rb and INK4 encode?

the Cdk inhibitor p16

Where do Rb and INK4 (encodes the Cdk inhibitor p1) regulate cell cycle progression?

at the same point as that affected by Cdk4, Cdk6, and

cyclin D which can all act as oncogenes

How does Rb inhibit passage through G1?

by repressing transcription of a number of genes involved in cell cycle progression and DNA synthesis

How does p53 regulate cell cycle progression?

DNA damage leads to transcription of cell cycle inhibitors, like p21, and proapoptotic genes if there is enough activated p53 present

Noncoding RNAs have become recognized as major regulators of

gene expression in what kind of cells and RNA's?

eukaryotic cells and both lncRNAs (long non-coding RNAs) and miRNAs can be dysregulated in cancer cells

What is the function of miRNAs?

target mRNAs to inhibit translation and induce degradation

How is miRNA seen as a potential involvement in cancer?

contribute to the regulation of approximately half of all protein-coding genes

How can miRNA's act as tumor suppressors?

expression of miRNAs is lower

What can lncRNAs result in?

as enhancers/promotors of transcription, repressors of

transcription, modify splicing of mRNAs, and even alter chromatin modifications (as in epigenetic changes)

Large-scale genome sequencing of thousands of individuals with

cancers have identified ~____ genes mutated that contribute to tumor

development

150

How can cancer be dealed with?

1. prevent development of the disease

2. reliably detect early premalignant stages of tumor

development that could be easily treated

Traditionally, the drugs used in cancer treatment either ______ DNA

or DNA replication, but these drugs are ___ ______ and target

all cells

damage; inhibit; not specific