Adhesion to mammalian epithelia is one of the prerequisites that are essential to accomplish pathogenesis of Candida albicans in the mammalian host. In this context C. albicans is able to adhere to a plethora of different cell types providing different microenvironments for colonization. To study the response of C. albicans adhering to different surfaces on the transcriptional level we have established an in vitro adhesion assay exploiting confluent monolayers of the human colorectal carcinoma cell line Caco-2 or epidermoid vulvo-vaginal A-431 cells. Candida albicans very efficiently adheres to these epithelia growing as hyphae. Using whole-genome DNA microarrays comprising probes for almost 7000 predicted ORFs we found that transcriptional profiles of C. albicans adhering to Caco-2 or to A-431 cells, although very similar, still significantly differ from those of Candida cells adhering to plastic surfaces. Differences became even more obvious when comparing C. albicans cells either growing in an adherent manner or in suspension culture. Correspondingly, we found for several cell surface genes, including PRA1, PGA23, PGA7 and HWP1, an adhesion-dependent induction of transcription. Obviously, C. albicans is able to respond specifically to very subtle differences in the environment during adhesion to various growth substrates.

Antiestrogens are universally used to treat estrogen receptor-positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor β (TGFβ) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGFβ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGFβ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneic MLTR, antiestrogentreated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8 + T cells, and suppressed the generation of cytotoxic effector cells in a TGFβ-dependent manner.Furthermore, we documented induction of regulatory T cells in CD4 + T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGFβ neutralizing antibody. Our findings offer evidence that antiestrogen induces immunosuppression in the tumor microenvironment, through a TGFβ-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer. Cancer Res; 70(4); 1314-22.

TNF-α is a major inflammatory cytokine named for its ability to induce rapid hemorrhagic necrosis of experimental cancers. During efforts to harness this antitumor activity in cancer treatments in the 1980s, a paradoxical tumor-promoting role of TNF became apparent. The cellular and molecular complexity of mammalian tumor microenvironments makes these opposing effects difficult to study. The fruit fly Drosophila melanogaster provides a simpler model system for studying complex cellular and genetic interactions that lead to tumor formation and progression. The paper from Marcos Vidal's group shows that both the tumor-suppressing and tumor-promoting roles of TNF are conserved in Drosophila, and that oncogenic Ras is the switch. The links between inflammation and cancer are now more fully understood, but it is still not clear whether TNF has potential as a target or a therapeutic in malignant disease, or both. Research in an invertebrate organism may provide important insights.