Biology Reference
In-Depth Information
6. ROLE OF
b
-ARRESTIN-DEPENDENT CHEMOTAXIS IN
HEALTH AND DISEASE
The two main disease scenarios in which
b
-arrestin-dependent che-
motaxis has been implicated are tumor cell metastasis and inflammation.
Tumor metastasis requires migration of malignant cells from the original
tumor to other sites within the body. This process requires a number of che-
motactic signals that allow the cells to migrate to nearby vessels, enter the
vasculature, and extravasate at distal sites. Similarly, inflammation involves
recruitment of leukocytes and other inflammatory cells from the vasculature
to injured tissue, and numerous changes within the tissue such as epithelial
proliferation, extracellular matrix deposition, and functional alterations in
both the invading and host cells. Several studies over the last decade in tumor
cell lines have demonstrated that constitutive migration of many cancer cells
is dependent upon
b
-arrestin. Likewise, studies have demonstrated that cer-
tain inflammatory processes are impaired in the absence of
b
-arrestin-2. Fur-
thermore,
b
-arrestin-dependent regulation of actin cytoskeletal proteins and
signaling pathways that affect cell migration has been demonstrated in
human cancer cell lines and leukocytes.
Recent
in vivo
studies have shed more light on the multiple mechanisms
by which
b
-arrestins can promote tumor cell migration and metastasis.
Interestingly, these studies suggest that both tumor cell and host
b
-arrestin
play important roles in this process, and that
b
-arrestins are pro-metastatic in
some scenarios and antimetastatic in others. In many cases,
b
-arrestin com-
plexes described in the previous sections play a major role in the metastatic
progression of cancers
in vivo
. CXCR4, which we discussed earlier in this
chapter, is upregulated in numerous malignant cancers, and CXCL12 is
expressed in many of the tissues to which tumor cells commonly metastasize.
While CXCL12 monomers promote metastasis, CXCL12 dimers have
tumor suppressor functions, effectively inhibiting cell migration through a
b
-arrestin-independent pathway.
44
Thus, development of biased ligands
that act like CXCL12 dimers may have therapeutic value for the treatment
of some cancers.
Several reports have also indicated that
b
-arrestins are required for the
recruitment of immune cells to the airways during asthma. Influx of leuko-
cytes to the lungs was not only decreased in
b
-arrestin-2 knockout mice, but
in wild-type mice receiving knockout bone marrow. Thus, the role of
b
-arrestins in asthma appears to be mediating the chemotaxis of invading
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