제 14 장 암과 노화

제 14 장 암과 노화

Cancer and Aging

그림 14-1

Mutations in early embryonic development?

Normal cells Initiated cells Preneoplastic cells Tumor cells

Initiation Promotion Progression

Carcinogens, free radicals, radiation,

viruses Tumor promoters

Cancer Development (Carcinogenesis)

Alterations or mutations in the genetic code

Tumor ( 종양 )

benign tumor : a tumor stays in one place malignant tumor

Definition: cells that proliferate in defiance of normal controls (neoplastic) and are able to invade and colonize surrounding tissues (malignant)

Characteristics

1. uncontrolled growth 2. no apoptosis

3. no or little aging & differentiation 4. genetically unstable

5. invasive 6. metastasis

Causes of cancer

genetic : inherited or acquired through errors in DNA replication environment : carcinogens

Carcinogen: any agent that causes cancer radiation

carcinogens in food processing (benzopyrene, acrylamide…) environment (dioxin, asbestos, benzopyrene,…)

viruses

free radicals

ROS (reactive oxygen species)

Normal cells Initiated cells Preneoplastic cells Tumor cells

Initiation Promotion Progression

Carcinogens, radiation,

free radicals Tumor promoters

Cancer Chemoprevention

blocking or suppressing of the carcinogenic process by one or several compounds

(Sporn & Newton 1979, Wattenberg 1985)

Alterations or mutations in the genetic code

Representative chemopreventive phytochemicals and their dietary sources.

Adapted from Nature Reviews Cancer. 2003 3(10):768-780

Genes that affect cancer

Oncogene : mutant gene that promotes cancer

Anti-oncogene (tumor suppressor gene) : gene acting to prevent unwanted cell division

Mutant oncogenes have a positive effect and promote the

development of cancer cells. A single oncogenic mutation in only one of a pair of genes is sufficient to give and effect; that is,

mutations in oncogenes are dominant and the second, wild-type copy of the gene cannot make up for the defect.

Tumor suppressor genes have a negative effect on cancer development. To allow cancers to grow, both copies of a tumor suppressor gene must be inactivated by mutation.

그림 14-3

Proto-oncogene : the “good” form of an oncogene. Original, healthy, unmutated version. The wild type. Necessary for the growth and

division of the cell.

oncogene

Cellular oncogene (c-onc) vs Viral oncogene (v-onc)

Cancer-causing retrovirus

Retrovirus

Cell communication Transformation

In cancer biology : conversion of a normal cell to a cancer cell

In molecular biology : uptake of a pure DNA by bacteria or animal cells

그림 14-6 Cancer cells are uninhibited

Transgenic mouse : mouse that is transformed with a foreign gene Knockout mouse (K/O mouse) : a genetically engineered mouse in

which researchers have inactivated, or “knocked out” an existing gene by replacing it or disrupting it with and artificial piece of DNA (insertion of gene cassette), ex) Nrf2 K/O mouse

그림 14-8

ras proto-oncogene -> ras oncogene : change in the structure

ras gene

- small GTPase

- involved in cellular signal transduction - Rat sarcoma (cf. carcinoma vs sarcoma)

- when switched on by incoming signals, it turns on genes involved in cell growth, differentiation and survival

- mutations in ras genes can lead to the production of permanently activated Ras proteins, which can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals - These signals result in cell growth and division, ultimately lead to cancer.

- Ras is the most common oncogene in human cancer (20-25% of all human tumors and up to 90% in certain types of cancer. eg.

Pancreatic cancer)

- For this reason, Ras inhibitors are being studied as a treatment for cancer, and other diseases with Ras overexpression.

receptor

Incoming signals

그림 14-11

과활성 상태로 고정

→ 지속적 세포분열 신호

Over activation

myc gene

- a regulator gene coding for a transcription factor

- a mutated version of Myc is found in many cancers, which Myc to be constitutively expressed

- This leads to the unregulated expression of many genes, some of which are involved in cell proliferation, and results in the formation of cancer.

- Malfunctions of Myc have been found in Burkitt’s lymphoma, carcinoma of the cervix, colon, breast, lung and stomach.

- Myc regulates expression of 15% of all genes through binding on consensus sequences (enhancer box sequences).

그림 14-12

myc oncogene : involved in cell proliferation

overexpression of Myc proteins by 1. multiple replication

2. constant expression Over expression

myc oncogene : involved in cell proliferation

over expression of Myc proteins by 1. multiple replication

2. constant expression

translocation

그림 14-14

Signal transmission (transduction) : normal function of proto-oncogenes

Growth factor Receptor

Transcription factor

Signal transmission protein

: protein kinases (regulation of enzymes or proteins)

Protein kinases : add phosphate to other enzymes or proteins (phosphorylation).

- Phosphorylation results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins.

- usually activation of enzymes or proteins

- Human genome contains about 500 protein kinase genes

-Up to 30% of all human proteins may be modified by kinase activity

-Kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

그림 14-16

Tumor suppressor genes : suppress uncontrolled cell growth or proliferation.

inactivation of both copies is required.

Null mutation

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Zinc finger of tumor suppressor proteins

그림 14-20

Regulation of cell cycle

Cyclins : proteins that regulate cell cycle CDK : cyclin dependent kinase

Cyclin + CDK -> activation of CDK -> addition of phosphate to related proteins -> cell division

Tumor suppressor genes : p53, p21, p16

p53

: regulates (arrest) cell cycle at the G2/S point on DNA damage recognition : activate DNA repair proteins when DNA has sustained damage

: initiate apoptosis (programmed cell death) if DNA damage proves to be irreparable : frequently found mutated in cancer cells

: tetramer

p21 : is activated by p53 upon DNA damage, arrest cell cycle p16 : inhibit cyclin E to arrest cell cycle

그림 14-23

Development of colon carcinoma

Tumor suppressor gene

Tumor suppressor gene

Tumor suppressor gene oncogene

그림 14-26

Metastasis of cancer cells

그림 14-28

Tumor necrosis factor (TNF)

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