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10 1023@a@1023725029589 PDF
10 1023@a@1023725029589 PDF
Introduction
The focal adhesion kinase (FAK) was initially
identied as a tyrosine phosphorylated protein in
cells transformed by the Src oncogene, and was
later found to associate with Src via an SH2
domain mediated interaction [13]. Using a PCR
based cloning strategy, FAK was independently
identied as a tyrosine kinase that was expressed in
a high grade sarcoma [4]. Thus, since its original
isolation from both a model system for cancer and
tumor tissue, FAK has been considered a candidate signaling protein that might function in the
development of human cancer.
The FAK gene is located on human chromosome 8q24, in proximity to the c-myc locus [5,6].
FAK is an essential gene product as FAK null
mice exhibit embryonic lethality [7]. Under normal
conditions, FAK controls a number of biological
processes including cell spreading, proliferation,
survival and motility [8,9]. Deregulation of several
of these processes is associated with malignancy. It
* Corresponding author.
E-mail: crispy4@med.unc.edu
is therefore easy to envision how aberrant regulation of FAK signaling could contribute to the
progression of a cancerous phenotype.
In normal cells, tyrosine phosphorylation and
activation of the catalytic activity of FAK are
regulated by many stimuli, but the major regulators
of FAK activity are the integrins, transmembrane
receptors for proteins of the extracellular matrix
[8,9]. Upon integrin-dependent cell adhesion, FAK
co-localizes with the integrins at focal adhesions,
sites of close contact with the extracellular matrix,
and becomes tyrosine phosphorylated and activated. Changes in integrin expression have been
observed in many cancers [1012]. In a number of
experimental systems, modulation of integrin
expression has altered the phenotypes of cancer
cells [13]. Integrin-mediated signaling events are
very likely responsible for the phenotypic changes
observed. As a major integrin regulated signaling
molecule, FAK may function downstream of
integrins in altering the phenotypes of cancerous
cells, a hypothesis that remains to be tested.
360
361
Breast
PI
+/
+
+++
+++
+++
+/
Colon
+
+
+
+/
Method
Reference
+++
+++
+++
+/+++
++++
++++
Northern
Western
IHC
IHC
[39]
[25]
[26]
[27]
++++
+++
+++++
+++
+++
Northern
Western
Western
IHC
Western, IHC
IHC
[39]
[25]
[28]
[26]
[29]
[27]
+++
+++
++/+++
Thyroid
+/+++***
++++
Western
[30]
Prostate
+/
+/+++
+
+/+++
+++
+
+++
+++
+++
RT-PCR, Western
IHC
[31]
[32]
Oral cavity**
/++
+/+++
+/++++
IHC
[33]
Liver
+
+/
+++
+++++
++/+++
Western
RT-PCR
IHC
[25]
[40]
[27]
Stomach
+/
++/+++
IHC
[27]
Ovary
++++
Western
[34]
Sarcoma**
++
+/
++++
Western
[25]
Brain/astrocytes
Western
IHC
IHC
Western
[35]
[36]
[37]
[38]
FISH
[6]
+
Head neck
++
+
++
+++
>2 copies
+++++
++
++
Expression or amplication of FAK in tumors and normal tissue is indicated. Expression levels are relative within the cited experiment
and is dened using arbitrary units. N, normal; B, benign; PI, preinvasive; M, metastatic; IHC, immunohistochemistry; RT-PCR,
reverse transcriptase polymerase chain reaction; FISH, uorescent in situ hybridization.
** Evidence is compiled from various sarcomas or various oral cavity carcinomas.
*** Evidence from two types of invasive tumors: locally invasive/highly aggressive, metastatic.
362
Origin
Description
FAK level*
Evidence
Reference
Normal
Invasive
2 copies
46 copies
310 copies
FISH
FISH
FISH
[6]
[6]
[6]
310 copies
FISH
[6]
46 copies
FISH
[6]
T-cells
Normal
Transformed
Lower
Higher
Western
Western
[83]
[83]
B-cells
Normal
Transformed
Lower
Higher
Western
Western
[83]
[83]
RCEC
Caki-2
Caki-1
Normal
Non-invasive
Metastatic
Lower
Intermediate
Higher
mRNA blot
mRNA blot
mRNA blot
[84]
[84]
[84]
LNCaP
DU-145
PC-3
Prostate
Prostate
Prostate
Low tumorigenicity
Highly tumorigenic
Highly tumorigenic
Lower
Elevated
Greatly Elevated
[31,32]
[31,32]
[31,32]
NHF
WI-38
LS180
LS174T
COLO205
BT474
BT-20
RD
Mesenchymal
Mesenchymal
Colon cancer
Colon cancer
Colon cancer
Breast cancer
Breast cancer
Rhabdomyosarcoma
Untransformed
Untransformed
Transformed
Transformed
Transformed
Transformed
Transformed
Transformed
Lower
Lower
Intermediate
Intermediate
Intermediate
Higher
Higher
Higher
Western
Western
Western
Western
Western
Western
Western
Western
[25]
[25]
[25]
[25]
[25]
[25]
[25]
[25]
FAK expression in various cancer cell lines and some of the properties of the cell lines are shown. SCC, squamous cell carcinoma;
FISH, uorescent in situ hybridization; IHC, immunohistochemistry.
* Relative level of FAK within each study.
363
364
Treatment
FAK status
Biological effect
Reference
Melanoma
Arachidonic acid
metabolite
Increased phosphorylation
Increased spreading
[85]
Increased expression
Transient phosphorylation
Transient binding to b1 integrin
Increased expression
with progression
Increased expression
Increased spreading
Increased spreading
Increased adhesion
Increased adhesion
with progression
Increased adhesion
with progression
Decreased matrix adhesion
Decreased cell-cell adhesion
[101]
[86]
Melanoma
Highly metastatic Prostate carcinoma
Genistein intake
Retinoic acid
FN adhesion
Prostate carcinoma
Normal Breast epithelia
Hepatocellular carcinoma
Melanoma
Highly tumorigenic Prostate carcinoma (HT)
vs. Poorly tumorigenic Prostate carcinoma
Epidermoid carcinoma
(EGFR expressors)
Echistatin treatment
IGFBP-1 or RGD
treatment
RGD peptide treatment
Bcl2 expression
Expression of a6b1
deletion mutant
FN stimulus
EGF treatment
EGF treatment
Glioma
Temozolomide treatment
Increased expression
Rapid phosphorylation
Cleaved
v-Src expression
Transformed Fibroblasts
v-Src expression
Increased activity
Suspension
Suspension
v-Src expression
Increased phosphorylation
[102]
[87]
[88]
[89]
Loss of adhesion
Loss of adhesion
Apoptosis
Apoptosis
Inhibition of anoikis
Decreased migration
[90]
[91]
Increased migration
Increased migration
[95]
[52]
Loss of adhesion
Increased motility
Increased invasion
Increased invasion
[71]
Decrease invasion
(irradiation-induced)
Increased invasion
[96]
Decrease adhesion
Increased motility
Increased adhesion-independent
growth
Increased adhesionindependent growth
Adhesion-independent
growth
[47]
Metastasis
[98]
Induction of metastatis
[99]
[92]
[93]
[94]
[70]
[31]
[97]
[68,69]
In a number of cancer cells, specic stimuli produce changes in FAK signaling, including changes in the level of FAK expression,
tyrosine phosphorylation and proteolytic cleavage. In many instances, these changes in FAK signaling have been correlated with
changes in a biological response that may be controlled by FAK.
365
FAK status
Biological effect
Reference
Melanoma
Breast cancer
[44]
[43,45,46]
Apoptosis
Decrease adhesion independent
growth
Enhanced adhesion independent
growth
HGF-induced adhesion
independent growth and invasion
Inhibibiton of HGF-induced
adhesion independent growth
and invasion
Increase migration
Adhesion independent growth
Tumor in nude mice
Acquisition of adhesion
independent growth
Tumors in nude mice
Inhibition of anoikis
Inhibit migration
Inhibit migration
[100]
[51]
[37]
[53] *
Decrease migration
Decrease invasion
Inhibit CD151-mediated
migration and invasion
Enhanced EGF-mediated motility
and invasion
Inhibit invasion
Decrease lung metastasis
Inhibit tumor growth
Reduce tumor formation
[56]
Melanoma
Trigeminal
neurinoma
Fibroblasts
NSCL cancer
Fibroblasts
(Ras transformed)
MDCK
Astrocytoma
Increase expression by
overexpression
MDCK
Prostate carcinoma
Prostate carcinoma
(avb3 transfected)
Glioblastoma
Adenocarcinoma
Melanoma
(highly metastatic)
Fibroblasts
Epidermoid
(EGFR expressors)
Ovarian cancer
Melanoma
Carcinoma
Papilloma
[98]
[103]
[24]
[50]
[36]
[49]
[52]
[13]
[55]
[71]
[59,104,105] *
[61] **
[64] ***
[62]
In order to explore the role of FAK in cancer, FAK expression and/or signaling has been either impaired or enhanced in model systems
for cancer. Alteration in FAK signaling in these systems produced dened changes in biological properties associated with the cancer
phenotype.
* FAK also plays a role in MMP secretion/activation.
** correlates with changes in proliferation.
*** involvement of urokinase receptor signaling.
366
367
368
369
Figure 2. Model of FAK involvement in tumor progression. In normal epithelium and benign hyperplasias, FAK is expressed at low
levels. In preinvasive, invasive and metastatic lesions, FAK is overexpressed (dark cells). Through its ability to regulate cell survival,
growth, migration and invasion, FAK may inuence tumor cell behavior and therefore promote malignancy.
Conclusions
In the normal tissues that have been characterized,
FAK expression is relatively low, whereas FAK is
overexpressed in early preinvasive lesions and is
highly expressed in metastatic lesions. Therefore,
FAK expression could serve as a prognostic tool
and may allow for accurate diagnosis and administration of appropriate treatments. In addition,
FAK may be useful as a therapeutic target, since
inhibition of FAK signaling can impair tumor
growth and metastasis. In some studies, inhibition
370
Acknowledgements
We would like to thank the members of the lab for
their helpful comments and suggestions during the
preparation of this review. Research in the
corresponding authors laboratory is supported
by National Institute of Health grants CA90901
and GM59943, and P60-DE13079 from the
National Institute for Dental and Cranial
Research (to M.D.S.). V.G.-N. is supported by a
pre-doctoral assistantship from the Department of
Defense (DAMD 17-00-1-0377).
5.
6.
7.
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9.
10.
11.
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16.
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