Tumor-associated inflammation can induce various molecules expressed from the tumors themselves or surrounding cells to create a microenvironment that potentially promotes cancer development. Inflammation, particularly chronic inflammation, is often linked to cancer development, even though its evolutionary role should impair nonself objects including tumors. The inflammation amplifier, a hyperinducer of chemokines in nonimmune cells, is the principal machinery for inflammation and is activated by the simultaneous stimulation of NF-kB and STAT3. We have redefined inflammation as local activation of the inflammation amplifier, which causes an accumulation of various immune cells followed by dysregulation of local homeostasis. Genes related to the inflammation amplifier have been genetically associated with various human inflammatory diseases. Here, we describe how cancer-associated genes, including interleukin (IL)-6, Ptgs2, ErbB1, Gas1, Serpine1, cMyc, and Vegfa, are strongly enriched in genes related to the amplifier. The inflammation amplifier is activated by the stimulation of cytokines, such as TNF-a, IL-17, and IL-6, resulting in the subsequent expression of various target genes for chemokines and tumor-related genes like BCL2L11, CPNE7, FAS, HIF1-a, IL-1RAP, and SOD2. Thus, we conclude that inflammation does indeed associate with the development of cancer. The identified genes associated with the inflammation amplifier may thus make potential therapeutic targets of cancers. Cancer Res; 74(1);

Hayano et al. show that Netrin-4, which is originally identified as an axon guidance molecule, is capable of enhancing sensitivity to sensory input and can contribute to neuropathic pain. The findings provide evidence for a previously unknown pain-inducing signal from spinal cord interneurons.

Some recent reports have revealed that the long scintigraphic appearance time (SAT), defined as the time between radionuclide injection and first sentinel lymph node (SLN) visualization in lymphoscintigraphy, is a negative predictive parameter of nodal metastasis in patients with melanoma. However, most of the methods used to measure the SAT were ambiguous because they utilized visualization in lymphoscintigraphy. We herein introduce a novel method by which to measure the SAT and lymphatic flow rate. The data of 33 patients with primary skin cancer were used. Sequential images were obtained using dynamic lymphoscintigraphy, and a time-activity curve of the SLN was created. The time at which the counts reached plateau was newly defined as an alternative to the SAT and was termed the scintigraphic saturation time (SST). The figure obtained by division of the distance by the SST was newly defined as an alternative to the lymphatic flow rate and termed the lymphatic transit rate (LTR). The SST was clearly determined. It ranged from 220 to 1430 s (mean, 805 s). Pathological examination revealed nodal metastasis in five patients. In 28 patients without metastasis, the mean LTR was in the order of lower limbs (4.07 AE 0.35 cm/min), upper limbs (2.67 AE 0.33 cm/min), trunk (1.79 AE 0.47 cm/min), and head and neck (1.11 AE 0.22 cm/min). The LTRs were higher in patients with nodal metastasis than those without. This method may be effective for accurate measurement of the SAT and lymphatic flow rate.

The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a “gateway” at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.