Spotlight

Abstract

O'Sullivan et al., pp. 1930–1940 PAK proteins, a family of serine/threonine p21-activating kinases, are critical effectors that link RhoGTPases to cell proliferation and cytoskeleton reorganization. PAK1 is the best characterized member of the PAK family, which also includes PAK2, PAK3 and PAK4 proteins. PAK1 gene amplifications and increased protein expression have been associated with breast, ovarian and colorectal carcinomas. In this issue of IJC, researchers from the Cork Cancer Research Center in Ireland identify PAK1 as a potential new drug target in kidney cancer. Renal cell carcinoma arises from the renal tubules and is the most common form of kidney cancer in adults. Notoriously resistant to chemotherapy and radiotherapy, it has been treated with some success by immunotherapy. The identification of PAK1 adds the possibility of yet another treatment option for this highly refractory tumor. O'Sullivan and colleagues discovered that PAK1, but not PAK2 or PAK3, was markedly overexpressed in several renal cell lines. Overexpressed PAK1 was hyperphosphorylated at threonine 423, a residue recognized by the phosphoinositide-dependent kinase 1 (PDK1) and required for full kinase activity. Expression of PAK1 and phospho-PAK1 was confirmed in tumor samples and correlated well to tumor stages. Introduction of a dominant-negative form of PAK1 or RNAi-mediated knockdown of the protein in 786-0 renal cancer cell lines decreased cell proliferation and anchorage-independent cell growth in vitro. Importantly, expression of dominant-negative PAK1 prevented growth of renal tumors in athymic MF1 nu-nu mice. These data support the model that therapeutic inhibition of PAK1 could become a critical new component in the treatment of patients with renal cell carcinoma. Kanagawa et al., pp. 2013–2022 Colorectal cancer represents one the leading causes of cancer deaths in the western world. While early diagnosis and prevention have made a significant difference, 20% of patients present with inoperable cancer at diagnosis and 50% of patients that undergo a potentially curative surgical resection relapse. New targeted therapeutic strategies are therefore needed. There is growing evidence that immune mechanisms have a prognostic significance in colorectal carcinoma. In particular, the presence of a tumor lymphocytic infiltrate appears to be significant. In this issue of the IJC, Kanagawa and colleagues tested the effect of several chemokines in a murine model of preexisting CT26 colon carcinoma. Chemokines regulate leukocyte trafficking and infiltration at local sites and are attractive candidates for cancer immunotherapy. Mice carrying a CT26 tumor were injected at the tumor site with adenovirus vectors expressing individual chemokines. The authors report that expression of CCL17 induced tumor regression and generated specific immunity in rechallenge experiments. These effects of CCL17 were dependent both on the vector dose and the number of injections. CCL17 expression in tumors was associated with significant increases in the number of infiltrating macrophages and CD8 T cells at the tumor sites. These observations warrant further investigation of the potential immunotherapeutic role of CCL17 in colorectal cancer in humans. Lambert et al., pp. 2052–2059 In the past 50 years, impressive progress has been made in the treatment of cancers of the colon and rectum. Patient survival has increased for both cancers due to improved patient care. However, it remained unclear how such progress affected patient survival: were more patients “cured” or did the survival time of the “uncured” increase? Using data from the Finish Cancer Registry, Lambert and colleagues show that both are true. In the years from 1953 to 2003, cure fractions and median survival of the uncured group increased in both cancers. The cure fractions are now broadly similar, but median survival of the uncured remains higher for cancer of the rectum. A reason could be that metastatic disease has been the predominant cause of death in colon cancer patients whereas rectal cancer patients often experience local recurrence, which is slower and now accessible to treatment. Postoperative mortality decreased after the introduction of intensive care units during the late 1960s and early 1970s. Combination chemotherapy became available in the late 1980s and early 1990s, and recently, surgeons have started to resect metastases in the liver. These factors have likely promoted the constant improvement in patient care. However, survival rates for patients with rectal cancer have not increased further in the past 5 years. In addition, the cure rate of colon cancer, which experienced a steep linear increase for patients above 70 years, was less improved in patients younger than 50 years. These factors indicate that cancer patient survival might plateau rather than further increase unless new curative treatments are found.