Spotlight

Abstract

Nielsen et al., pages 2086–2095 Ductal carcinoma in situ (DCIS) is an early lesion, in which all the cancer cells are still confined within the ducts of the breast and prognosis is still very good. But once tumor cells manage to leave the confines of the ducts and slip into the surrounding fatty and connective tissue of the breast, survival rates start to drop. Naturally, researchers are particularly interested in the molecular mechanisms that put neoplastic cells on a metastatic trajectory. The transition from DCIS to invasive ductal carcinoma starts in microinvasive foci and requires the proteolytic degradation of the surrounding basement membrane. In a previous study, Nielsen et al. found that the expression of matrix metalloproteinase 13 (MMP-13) accompanies the formation of these foci. Now, they turned their attention to plasminogen activators (PAs), which generate plasmin, a potent protease, from its proenzyme plasminogen. Two key proteins required for cell-mediated plasminogen activation, uPA (urokinase-type PA), and its receptor, uPAR, were focally upregulated in stromal cells at the sites where invasion first takes place, suggesting an important role for the plasminogen activation system in the transition from DCIS to invasive carcinoma. The authors based their conclusions on the examination of 9 DCIS lesions with and 9 DCIS lesions without microinvasion. Double immunoflourescence analysis of uPA (shown in green) and uPAR (shown in red) immunoreactivity in DCIS. In the microinvasive area shown in (a-c, *), in which early invasion was identified on an adjacent section, uPA and uPAR are colocalized in numerous stromal cells. uPA immunoreactivity (d and g) strongly overlaps with uPAR immunoreactivity (e and h) on the surface of macrophage-like cells (d-f, arrows) and myofibroblasts (g-i, arrows). MMPs were considered to be of critical importance in tumor invasion and metastasis. Spurred by these findings, the pharmaceutical industry produced several orally active MMP inhibitors. Ultimately, however, all of them failed in clinical trials. The current study suggests that functional compensation by the uPA system may be to blame and in order to be successful, future therapies based on proteinase inhibitors would have to target several proteolytic systems. Quaglia et al., pages 2196–2201 Europe's population is aging rapidly. In a few years, the leading edge of baby-boomers, born after World War II, will start to turn 65. It is estimated that within the next 25 years, today's number of people over 65 will have doubled and the burden of cancer in elderly people will rise accordingly. Unfortunately, the prognosis of elderly patients has always been poorer than that of younger adults. Quaglia et al. dug deeply into data collected between 1990 and 1994 as part of the EUROCARE project, an international collaborative study on the survival of cancer patients in Europe, to compare the prognosis of elderly patients (aged 65 to 84) with that of younger patients (aged 55 to 64). Independent of the cancer site, middle-aged patients generally fared much better than older patients and the survival advantage commonly observed in women compared to men was diminished in the elderly. Interestingly, most of the excess mortality of elderly patients was confined to the first year after diagnosis, particularly for women. The authors speculate that these differences might be due to tumors being diagnosed at more advanced stages in this cohort, frailty increasing the mortality related to treatment and the fact that elderly patients are less likely to be referred to clinical trials. However, patients over 65 who survived this critical period had slightly better odds of surviving the next 4 yours than younger adults. This large gap in initial survival rates is not observed in the U.S. and more detailed studies will be necessary to uncover the reasons. Zhao et al., pages 2208–2213 Isothiocyanates (ITCs), plant-derived sulfur-containing compounds, give broccoli and other cruciferous vegetables such as cabbage their typical flavor and make them unpalatable for many people. But study after study has hinted at their ability to inhibit cell proliferation in vitro and reduce the risk of carcinogen-induced tumors in animals. Epidemiological studies in humans have shown that a diet rich in ITC-containing cruciferous vegetables lowers the risk of lung and esophageal cancer. These studies also suggested a gene-environment interaction, with people deficient for the GSTM1 (glutathione S-transferase, Mu-1) or GSTT1 (glutathione S-transferase, Theta 1) benefiting even more from the consumption of cruciferous vegetables. To investigate whether the same holds true for bladder cancer – after all, the epithelium lining the bladder is the tissue with the greatest exposure to ITCs – Zhao et al. evaluated the dietary intake of ITCs from cruciferous vegetables, GSTM1, GSTT1 and N-acetyltransferase 2 (NAT2) and bladder cancer risk in a case-control study with 697 patients and 708 healthy controls. Consumption of ITCs reduced the risk of bladder cancer in a dose-dependent manner, with older individuals and heavy smokers gaining the most from their consumption.