In this issue

Abstract

Suppression of the immune system is a problem faced by many cancer patients, especially those whose diseases are in an advanced stage. Elucidating the mechanism(s) behind this immunosuppression would be beneficial in trying to counter it and bolster immune response to tumors. To this end, Takahashi et al. are studying the effects of macrophages in tumor-draining lymph nodes (MTDL) on T-cell apoptosis and comparing these effects among patients with early and advanced stage gastric cancer. In their paper on pages 393–399 they report two interesting findings. Firstly, they note that, in patients with advanced stage gastric cancer, MTDL induce T-cell apoptosis, elevate caspase-3 activity in peripheral T-cells, reduce expression of signal transducing TCR ζ molecules and impair production of IFN ζ. Secondly, they note that MTDL from patients with advanced stage gastric cancer are qualitatively different from those with an early stage of the disease: they exhibit an increased production of hydrogen peroxide and elevated production of intracellular IL-10 and IL-12. Hydrogen peroxide had been known to induce T-cell apoptosis; however, the presence of catalase, a selective scavenger of hydrogen peroxide, did not prevent MTDL downregulation of TCR ζ. This then must occur by another mechanism. Even so, this paper supports the notion that normalization of T-cell function by anti-oxidant therapy is an advantageous course of study. Carcinoembryonic antigen (CEA) is a 180- to 200-kDa glycoprotein, expressed by various types of neoplasms, that is widely used as a human tumor marker. Clinical trials have investigated the possibility that CEA may be used as a target antigen for active specific immunotherapy of patients with colorectal carcinoma. Unfortunately, the use of CEA-directed vaccines has thus far been unsuccessful in controlling cancer progression in humans. One hypothesis for this failure is that CEA is expressed heterogeneously in the tumor. Thus, pharmacological or biological agents that may increase the expression of CEA and MHC molecules have been sought. The anti-metabolite 5-fluorouracil (5-FU) has been shown to upregulate CEA and MHC expression in various colon and breast carcinoma cell lines in vitro, although the mechanism(s) responsible for this upregulation remain unknown. In their report on pages 437–445 of this issue, Correale et al. extend the ramifications of these findings by demonstrating that 5-FU treatment enhances cancer cell susceptibility to the lytic effects of CEA peptide-specific cytotoxic T-cells. Kaplan-Meier plotting of overall (p = 0.0012) and disease-free (p = 0.0033) survival of SMAD7 deletion. Boulay et al. studied the influence of each of these genes on the clinical outcome of patients suffering from colorectal cancer, and their results are published on pages 446–449. They had previously defined SMAD4 deletion as a negative predictive marker for a benefit of chemotherapy. They observed no clinical relevance for SMAD2 deletion, but SMAD7 deletion had a low hazard ratio for both relapse and death, while its amplification had a hazardous effect on survival. Given that SMAD7 is the only SMAD specifically inhibitory for TGFβ, these data suggest that SMAD7 deletion may enhance sensitivity to the tumor suppressor activity of TGFβ and confirm the hypothesis that resistance to TGFβ-mediated apoptosis is an important factor in the expansion of colorectal carcinoma. Effect of ATN-161, with or without 5-FU, on vessel counts, tumor cell proliferation and tumor cell apoptosis. On pages 496–503 of this issue, Stoeltzing et al. hypothesize that the blocking of α5β1 binding to fibronectin by a different peptide antagonist, ATN-161, which does not affect cell adhesion, may show the same results. Furthermore, they suggest that α5β1 need not be expressed on the cancer cells to achieve these results, as the more sensitive target is the α5β1 on the activated endothelial cells. They also thought that chemotherapy with the anti-metabolite 5-fluorouracil (5-FU) might synergize with the anti-angiogenic effects of the peptide to inhibit angiogenesis and the growth of liver metastases in a murine model. As their report demonstrates, they were correct in all of their hypotheses; not only did the combination therapy increase tumor cell apoptosis, decrease tumor cell survival and reduce the formation of liver metastases, it improved survival in a murine colon cancer model.