Focal adhesion kinase and cancer

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that resides at the sites of integrin clustering, known as focal adhesions. The FAK protein has a molecular mass of 125kDa and is encoded by the FAK gene located on human chromosome 8q24. Structurally, FAK consists of an amino-terminal regulatory FERM domain, a central catalytic kinase domain, two proline-rich motifs, and a carboxy-terminal focal adhesion targeting domain. FAK has been shown to be an important mediator of cell growth, cell proliferation, cell survival and cell migration, all of which are often dysfunctional in cancer cells. Our lab was the first to isolate FAK from primary human tissue and link it to the process of tumorigenesis. We analyzed FAK mRNA expression in normal, invasive and metastatic human tissues and demonstrated through Northern blot analysis that normal tissues had very low levels of FAK mRNA while primary and metastatic tumors significantly overexpressed FAK. We also demonstrated and confirmed FAK overexpression in colorectal carcinoma and liver metastases with real-time PCR. In this review we summarized immunohistochemical data of FAK expression and role in different cancer types tumors and discussed FAK inhibition therapy approaches

Analysis of steroid hormone effects on xenografted human NF1 tumor Schwann cells

The neurofibroma, a common feature of neurofibromatosis type 1 (NF1), is a benign peripheral nerve sheath tumor that contains predominantly Schwann cells (SC). There are reports that neurofibroma growth may be affected by hormonal changes, particularly in puberty and pregnancy, suggesting an influence by steroid hormones. This study examined the effects of estrogen and progesterone on proliferation and apoptosis in a panel of NF1 tumor xenografts. SC-enriched cultures derived from three human NF1 tumor types [dermal neurofibroma, plexiform neurofibroma and malignant peripheral nerve sheath tumor (MPNST)] were xenografted in sciatic nerves of ovariectomized scid/Nf1−/+ mice. At the same time, mice were implanted with time-release pellets for systemic delivery of progesterone, estrogen or placebo. Proliferation and apoptosis by the xenografted SC were examined two months after implantation, by Ki67 immunolabeling and TUNEL. Estrogen was found to increase the growth of all three MPNST xenografts. Progesterone was associated with increased growth in two of the three MPNSTs, yet decreased growth of the other. Of the four dermal neurofibroma xenografts tested, estrogen caused a statistically significant growth increase in one and progesterone did in another. Of the four plexiform neurofibroma SC xenografts, estrogen and progesterone significantly decreased growth in one of the xenografts, but not the other three. No relationship of patient age or gender to steroid response was observed. These findings indicate that human NF1 Schwann cells derived from some tumors show increased proliferation or decreased apoptosis in response to particular steroid hormones in a mouse xenograft model. This suggests that antiestrogen or anti-progesterone therapies may be worth considering for specific NF1 neurofibromas and MPNSTs

The AO Spine Thoracolumbar Injury Classification System and Treatment Algorithm in Decision Making for Thoracolumbar Burst Fractures Without Neurologic Deficit.

STUDY DESIGN Prospective Observational Study. OBJECTIVE To determine the alignment of the AO Spine Thoracolumbar Injury Classification system and treatment algorithm with contemporary surgical decision making. METHODS 183 cases of thoracolumbar burst fractures were reviewed by 22 AO Spine Knowledge Forum Trauma experts. These experienced clinicians classified the fracture morphology, integrity of the posterior ligamentous complex and degree of comminution. Management recommendations were collected. RESULTS There was a statistically significant stepwise increase in rates of operative management with escalating category of injury (P < .001). An excellent correlation existed between recommended expert management and the actual treatment of each injury category: A0/A1/A2 (OR 1.09, 95% CI 0.70-1.69, P = .71), A3/4 (OR 1.62, 95% CI 0.98-2.66, P = .58) and B1/B2/C (1.00, 95% CI 0.87-1.14, P = .99). Thoracolumbar A4 fractures were more likely to be surgically stabilized than A3 fractures (68.2% vs 30.9%, P < .001). A modifier indicating indeterminate ligamentous injury increased the rate of operative management when comparing type B and C injuries to type A3/A4 injuries (OR 39.19, 95% CI 20.84-73.69, P < .01 vs OR 27.72, 95% CI 14.68-52.33, P < .01). CONCLUSIONS The AO Spine Thoracolumbar Injury Classification system introduces fracture morphology in a rational and hierarchical manner of escalating severity. Thoracolumbar A4 complete burst fractures were more likely to be operatively managed than A3 fractures. Flexion-distraction type B injuries and translational type C injuries were much more likely to have surgery recommended than type A fractures regardless of the M1 modifier. A suspected posterior ligamentous injury increased the likelihood of surgeons favoring surgical stabilization