Learning Objectives After completing this course, the reader will be able to: Discuss the role of TNF‐a in cancer survival and apoptosis. Describe the mechanism of chemotherapy potentiation by TNF‐a. Explain the selective targeting of tumor vasculature by TNF‐a. Discuss TNFR‐1 and TNFR‐2 signaling. Access and take the CME test online and receive 1 AMA PRA category 1 credit at http://CME.TheOncologist.com Tumor necrosis factor alpha (TNF‐α), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. Although named for its antitumor properties, TNF has been implicated in a wide spectrum of other diseases. The current use of TNF in cancer is in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas and other irresectable tumors of any histology to avoid amputation of the limb. It has been demonstrated in the isolated limb perfusion setting that TNF‐α acts synergistically with cytostatic drugs. The interaction of TNF‐α with TNF receptor 1 and receptor 2 (TNFR‐1, TNFR‐2) activates several signal transduction pathways, leading to the diverse functions of TNF‐α. The signaling molecules of TNFR‐1 have been elucidated quite well, but regulation of the signaling remains unclear. Besides these molecular insights, laboratory experiments in the past decade have shed light upon TNF‐α action during tumor treatment. Besides extravasation of erythrocytes and lymphocytes, leading to hemorrhagic necrosis, TNF‐α targets the tumor‐associated vasculature (TAV) by inducing hyperpermeability and destruction of the vascular lining. This results in an immediate effect of selective accumulation of cytostatic drugs inside the tumor and a late effect of destruction of the tumor vasculature. In this review, covering TNF‐α from the molecule to the clinic, we provide an overview of the use of TNF‐α in cancer starting with molecular insights into TNFR‐1 signaling and cellular mechanisms of the antitumor activities of TNF‐α and ending with clinical response. In addition, possible factors modulating TNF‐α actions are discussed.

TRPM7 encodes a Ca 2þ -permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. Cancer Res; 72(16); 4250-61. Ó2012 AACR.

In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT "plus-end-tracking proteins," or +TIPs, have been proposed to regulate selective MT stabilization, including the CLASPs, a complex of CLIP-170, IQGAP1, activated Cdc42 or Rac1, a complex of APC, EB1, and mDia1, and the actin-MT crosslinking factor ACF7. By using mouse embryonic fibroblasts (MEFs) in a wound-healing assay, we show here that CLASP2 is required for the formation of a stable, polarized MT array but that CLIP-170 and an APC-EB1 interaction are not essential. Persistent motility is also hampered in CLASP2-deficient MEFs. We find that ACF7 regulates cortical CLASP localization in HeLa cells, indicating it acts upstream of CLASP2. Fluorescence-based approaches show that GFP-CLASP2 is immobilized in a bimodal manner in regions near cell edges. Our results suggest that the regional immobilization of CLASP2 allows MT stabilization and promotes directionally persistent motility in fibroblasts.