Partners in crime: TNFα-based networks promoting cancer progression.

Current therapeutic approaches in malignancy are often based on combination therapies, reflecting present understanding of the way different players act together in cancer. The cooperative activity of several elements can potentiate the pro-metastatic functions of the cancer cells and of the tumor microenvironment (TME), together leading to a more aggressive disease phenotype. The design of improved therapeutic modalities requires better identification of networks that act at specific cancer-related settings, and of the molecular mechanisms involved. Such studies will indicate if therapies that co-target several factors or their receptors, simultaneously, could apply. Also, by delineating the intracellular pathways that are activated under such cooperative activities, it will be possible to determine whether to inhibit one specific molecular route that is shared by the different partners, or alternatively, design modalities that jointly target intracellular components acting in concert. This Focused Research Review illuminates the therapeutic relevance of this research field by describing our published findings in breast cancer-related publications, which identified networks that are established by the pro-inflammatory/pro-metastatic cytokine TNFα. It describes the additive/synergistic activities of TNFα with other soluble factors residing at the TME (e.g., IL-1β, TGFβ1, estrogen, EGF), with intracellular components such as the Ras oncogene, and with the tumor-stroma contexture through the activation of molecular cascades (Notch). The roles of the p65 (NF-κB) pathway-acting alone or in intricate relationships with other intracellular mechanisms-are described, the "TNFα-based network" is discussed as a general paradigm in malignancy and its clinical implications in cancer therapy are addressed.