The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 393

deaths will occur frombladder cancer in 2012. 58 Bladder cancer is initiated in
the epithelial cell layer lining the bladder lumen. Themajority of bladder can-
cer patients present with the superficial form. Unfortunately, recurrence,
invasion, and metastasis, even after seemingly successful treatment at very
early stages, are characteristic of bladder cancer. The need for life-long treat-
ment and surveillance makes it the most expensive cancer to treat on a per
patient basis. 66 We found that the b -isoform of the thromboxane receptor

(TP ) can cause malignant transformation in immortalized nontransformed

urothelial cells. 67 TP

b

, receptors have been found to interact
with ARRB2, 22-24 thus raising the possibility that the TP

b , but not TP a

isoform-specific
interaction with ARRB2 leads to the pathophysiologic effects seen in cancer
cells. ARRB2-RNA interference treatment of bladder cancer cells decreased
TP receptor agonist (U46619) dependent increases in cellmigration and inva-
sion. ARRB1-RNA interference knockdown did not alter agonist-
dependent stimulation of cell migration and invasion. These data represent
evidence of a role for ARRB2, but not ARRB1, in the malignant transfor-
mation and maintenance of the malignant phenotypes induced by TP

b

. 67 b

3.5. Hematological malignancies
Although the critical role of ARRBs in maintaining the transformed status of
many epithelial cells has been demonstrated in several studies, their role in
the initiation and progression of hematological malignancies is not well stud-
ied. Acute lymphoblastic leukemia (ALL) is the main subtype of childhood
leukemia. Standard treatment protocols used for ALL involve risk stratifica-
tion and risk-based therapy. These protocols ensure the use of low toxicity
protocols for low-risk patients and more aggressive treatment for high-risk
individuals. The risk stratification process utilizes several clinical and labo-
ratory features such as patient age, white blood cell count, and immuno-
logic subtype of the disease. 68 Genetic-based stratification of diseases is
proving increasingly more effective. Recently, two published reports
supported a potential role of ARRBs in hematological malignancies.
The first report studied the mRNA expression of ARRB1 in 155 newly
diagnosed children with ALL and correlated the expression with 51 con-
trols. 69 The expression of ARRB1 was significantly elevated in the ALL
patients and its levels were correlated with white blood cell count and risk
classification. Interestingly, the levels of ARRB1 also inversely correlated
with Notch1, which is essential for T-cells and developing hematological
cells. The second study investigated the role of ARRB1 and ARRB2 in