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73

MOLECULAR BIOLOGY OF CANCER

2.

A cancer cell can grow in the presence of normal growth-inhibiting signals issued
by neighboring cells.

3.

A cancer cell CANNOT activate apoptosis (i.e., programmed cell death; “cell sui-
cide”) in response to DNA damage.

4.

A cancer cell can stimulate blood vessel formation (i.e., angiogenesis).

5.

A cancer cell can acquire telomerase activity and become immortalized (i.e., no
mitotic limit).

6.

A cancer cell can alter its cell membrane receptors to metastasize into other areas
of the body.

D. CIN and defects in the MMR pathway are responsible for a variety of hereditary cancer

predisposition syndromes including hereditary nonpolyposis colorectal carcinoma,
Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia.

E.

Epigenetic factors have emerged to be equally damaging to the cell cycle control. In
this regard, hypermethylation of promoter regions for tumor-suppressor genes and
MMR genes cause gene silencing that contributes to oncogenesis.

Signal Transduction Pathways.

The consequence of an imbalance between the mech-

anisms of cell cycle control and mutation rates within genes is either the upregulation of
pro-oncogenic signal transduction pathways or the downregulation of anti-oncogenic sig-
nal transduction pathways. Some of the common signal transduction pathways that are
involved in oncogenesis or oncoprogression are indicated below.

A. MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY (Figure 11-5)

B. TRANSFORMING GROWTH FACTOR PATHWAY (Figure 11-6)

C. PHOSPHATIDYLINOSITOL 3-KINASE/PTEN/AKT PATHWAY (Figure 11-7)

III

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74

CHAPTER 11

FGF

FGF

FGFR

SOS

GNRP

GDP

RAS

GTP

Active RAS

RAF

MEK

ERK

Po

4

Po

4

Po

4

Po

4

GTP

Po

4

Po

4

ELK-1

Po

4

SRF

DNA

Transcription of FOS gene and JUN gene into

FOS mRNA and JUN mRNA

FOS and JUN proteins dimerize to form

AP-1 transcription faction

Transription of numerous

growth factor genes

DNA

AP-1

FOS

JUN

EARLY

RESPONSE

LATE

RESPONSE

FOS mRNA

JUN mRNA

FOS protein

JUN protein

Translation

● Figure 11-5 Mitogen-activated protein kinase (MAPK) pathway.

•

When FGF (fibroblast growth factor) binds to FGFR (fibroblast growth factor receptor), autophosphorylation (PO

4

) of

FGFR occurs.

•

This is recognized by SOS adaptor protein which activates GNRP (guanine nucleotide releasing factor).

•

GNRP (guanine nucleotide releasing factor) activates the G-protein RAS by transforming the bound GDP to GTP (RAS-
GDP S active RAS-GTP).

•

Active RAS-GTP attracts RAF kinase to the inner leaflet of the cell membrane and binds RAF kinase causing a three-
dimensional configurational change which activates RAF kinase.

•

Active RAF kinase phosphorylates MEK kinase.

•

Phosphorylated MEK kinase phosphorylates ERK kinase.

•

Phosphorylated ERK kinase enters the nucleus and phosphorylates the transcription factor ELK-1.

•

Phosphorylated ELK-1 complexes with SRF (serum response factor) leading to the transcription of immediate early
genes (called the early response), such as the FOS gene and JUN gene.

•

FOS and JUN mRNAs exit the nucleus and undergo translation to the FOS and JUN proteins.

•

FOS and JUN proteins enter the nucleus and dimerize to form the AP-1 transcription factor.

•

The AP-1 transcription factor leads to the transcription of late response genes (called the late response). The late
response genes include numerous growth factor genes.

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75

MOLECULAR BIOLOGY OF CANCER

● Figure 11-6 SMAD (Sma protein and Mad protein) pathway.

•

TGF

1 is a cytokine which acts as a tumor suppressor in the early stages of oncogenesis through the SMAD path-

way.

•

When TGF-

 binds to the Type II TGF- receptor, the Type II TGF- receptor binds the Type I TGF- receptor and

phosphorylates it.

•

The phosphorylated Type I and Type II TGF-

 receptor complex phosphorylates the R-Smad protein (receptor-regulated

Smad protein).

•

The phosphorylated R-Smad protein binds to Co-Smad protein (common partner Smad).

•

The heterodimeric Smad complex enters the nucleus.

•

The Smad complex works with other transcription factors.

•

This leads to the transcription of various genes some of which trigger apoptosis.

TGF-

β

1

R-Smad

R-Smad

Type II

Type I 

TGF-

β

1

R-Smad

Co-Smad

R-Smad

Co-Smad

DNA

TFs

TFs

R-Smad

Co-Smad

Transcription of

various genes

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76

CHAPTER 11

● Figure 11-7 PI3-K/PTEN/Akt pathway.

•

When IGF (insulin-like growth factor) binds to IGFR (insulin-like growth factor receptor), autophosphorylation (PO

4

)

of IGFR occurs.

•

PI3-K (phosphatidylinositol 3-kinase) binds to IGFR-PO

4

and catalyzes the conversion of PIP

2

(phosphatidylinositol 3, 4

biphosphate) to PIP

3

(phosphatidylinositol 3, 4, 5 triphosphate).

•

PTEN (phosphatase and tensin homolog) catalyzes the conversion of PIP

3

to PIP

2

. This dephosphorylation is important

because it inhibits the PI3-K/PTEN/Akt pathway.

•

PIP

3

recruits and serves as a docking site for Akt kinase (transforming retrovirus isolated from the Ak mouse strain)

and PDK1 (phosphoinositide-dependent protein kinase).

•

Akt is phosphorylated by PDK1 and thereby activated.

•

Activated Akt dissociates from the cell membrane and can affect a myriad of substrates via its kinase activity. Three
possible pathways are shown.

•

Activated Akt phosphorylates BAD (bcl-xl/bcl-2-antagonist which stimulates cell death). Protein 14-3-3 binds to
BAD-PO

4

which sequesters BAD. Sequestered BAD inhibits cell death (or apoptosis).

•

Activated Akt activates mTOR kinase (mammalian target of rapamycin) through a series of steps (not shown). Ac-
tivated mTOR stimulates cell growth by increasing protein synthesis.

•

Activated Akt phosphorylates GSK3

 (glycogen synthase kinase 3). GSK3-PO

4

is inactive. Inactive GSK3

-PO

4

stimulates cell proliferation by increasing 

-catenin levels (the penultimate downstream mediator of the WNT

signal pathway) and by increasing protein synthesis.

IGF

Po

4

Po

4

Inhibits

cell death

(aptosis)

PI3-K

PIP

2

PIP

3

AKt

PDK1

PDK1

AKt

PIP

3

Po

4

AKt

Stimulates

cell growth

Stimulates

cell proliferation

mTOR

BAD

BAD

Po

4

14-3-3

BAD

Po

4

14-3-3

14-3-3

GSK3

β

GSK3

β

Po

4

(Inactive)

PTEN

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77

Neutrophils (Polys, Segs, or PMNs) (Figure 12-1)

A. Neutrophils are the most abundant leukocyte in the peripheral circulation (50%–70%).

B. Neutrophils have a multilobed nucleus.

C. Neutrophils have larger primary (azurophilic) granules, which are endolysosomes that

contain acid hydrolases and myeloperoxidase (produces hypochlorite ions).

I

Chapter

12

Cell Biology of the Immune System

● Figure 12-1 Neutrophil. RBO 

 respiratory

burst oxidase.

D. Neutrophils have smaller secondary granules

that contain lysozyme, lactoferrin (partici-
pates in free radical generation), alkaline
phosphatase, elastase, and other bacteriosta-
tic and bacteriocidal substances. These 
substances are mainly released into the extra-
cellular environment.

E.

Neutrophils have respiratory burst oxidase (a
membrane-associated enzyme), which pro-
duces hydrogen peroxide (H

2

O

2

) and super-

oxide, which kill bacteria.

F.

Neutrophils are the first to arrive at an area of
tissue damage (within 30 minutes; acute in-
flammation), being attracted to the site by complement C5a and LTB

4

. The Complement

System consists of 20 plasma proteins synthesized by the liver that enhance the effect of an-
tibody binding to pathogens (called opsonization) so that neutrophils and macrophages may
phagocytosed them more easily.

G. Neutrophils are highly adapted for anaerobic glycolysis with large amounts of glyco-

gen to function in a devascularized area.

H. Neutrophils play an important role in PHAGOCYTOSIS of bacteria and dead cells by

using F

C

antibody receptors, C5 complement receptors, and bacterial lipopolysac-

charides to bind to the foreign material. Neutrophils must bind to the foreign material
to begin phagocytosis forming a phagocytic vacuole. The primary granules (mainly)
and secondary granules bind to the phagocytic vacuole and release their contents to
kill the foreign microorganism.

I.

Neutrophils impart natural (or innate) immunity along with macrophages and natural
killer (NK) cells.

J.

Neutrophils have a lifespan of 6–10 hours; 2–3 days in tissues.

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