Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.

FDG-PET is a valuable tool for the noninvasive assessment of histopathologic tumor response after neoadjuvant radiotherapy and chemotherapy.

Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, D-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of D-1MT, this cannot be attributed to inhibition of IDO in tumor cells.

The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.

Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon. [Cancer Res 2007;67(18):8615-23]

BackgroundCarcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called “sporadic,” because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers.Presentation of hypothesisOur paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche.Testing the hypothesisIf, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell.Implication of the hypothesisThe paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.

This study aimed to address the relative contributions of the proinflammatory cytokine interleukin‐6 (IL‐6) and the cytokine‐like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)‐induced systemic inflammation. Wildtype and IL‐6KO mice were injected with LPS (50 μg/kg, intraperitoneally) and the brains analyzed by immunohistochemistry and reverse‐transcriptase polymerase chain reaction (RT‐PCR). LPS induced a pronounced nuclear translocation of the signal transducer and activator of transcription (STAT3) throughout the brains of wildtype mice, an effect that was significantly diminished, but not abolished, in the IL‐6KOs. The remnant STAT3‐activation, although still observed within some of the same areas activated by IL‐6, was most intense in ependymal and meningial cells and along distinct blood vessels throughout the brain. This expression was almost totally abolished in the presence of an anti‐leptin antiserum. Interestingly, the induction of cyclooxygenase 2 and microsomal prostaglandin E synthase (mPGES), the rate‐limiting enzymes for synthesis of PGE2 by LPS, was diminished to a degree that correlated with the absence of IL‐6 but not entirely with leptin. These results demonstrate that the induction of the inflammatory pathway in the brain is mediated by both IL‐6 and leptin, which appear to work in tandem. Unlike IL‐6, however, the contribution of leptin to this response was limited to distinct cell types/brain areas and STAT3‐responsive target genes implicated in the brain‐controlled sickness‐type response. The physiological significance of leptin's action on meningeal and endothelial cells remains to be clarified but might reflect a role in LPS‐induced immune cell infiltration into the brain. J. Comp. Neurol. 511:373–395, 2008. © 2008 Wiley‐Liss, Inc.

Despite advances in neoadjuvant and adjuvant therapy, attention to proper surgical technique, and improved pathological staging for both the primary and metastatic lesions, almost half of all colorectal cancer patients will develop recurrent disease. More concerning, this includes ~25% of patients with theoretically curable node-negative, non-metastatic Stage I and II disease. Given the annual incidence of colorectal cancer, approximately 150,000 new patients are candidates each year for follow-up surveillance. When combined with the greater population already enrolled in a surveillance protocol, this translates to a tremendous number of patients at risk for recurrence. It is therefore imperative that strategies aim for detection of recurrence as early as possible to allow initiation of treatment that may still result in cure. Yet, controversy exists regarding the optimal surveillance strategy (high-intensity vs. traditional), ideal testing regimen, and overall effectiveness. While benefits may involve earlier detection of recurrence, psychological welfare improvement, and greater overall survival, this must be weighed against the potential disadvantages including more invasive tests, higher rates of reoperation, and increased costs. In this review, we will examine the current options available and challenges surrounding colorectal cancer surveillance and early detection of recurrence.