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Background: The growth of cancer cells in inflammatory tissue is often observed. This can be the result of favorable conditions for endothelial cell adherence and/or increased production of local growth factors.Purpose: The role of the proinflammatory cytokine interleukin 1 (IL-1) in the prometastatic and growth-promoting environment of inflammation was studied in vivo, and the mechanism of cytokine action was studied in vitro as well.Methods: Systemic inflammation was induced by the intravenous injection of IL-1 beta or lipopolysaccharide (LPS), and the hepatic metastasizing ability of B16 melanoma (B16) cells following intrasplenic injection was studied. IL-1 receptor blockade was accomplished with the use of the IL-1 receptor antagonist (IL-1Ra). In vitro, IL-1Ra was used to assess the mechanism for prometastasis and growth promotion of cultured hepatic sinusoidal endothelium stimulated with LPS.Results: There was a statistically significant (P < .01) enhancement in the parameters of hepatic metastasis when B16 cells were injected intrasplenically either 4 hours after IL-1 injection or 6 or 12 hours after LPS injection. IL-1Ra pretreatment reduced IL-1-induced enhancement of metastasis by 73%-87% and completely inhibited the augmentation of metastasis following LPS injection. In vitro, the adherence of melanoma cells to LPS-treated endothelium increased nearly twofold but was completely abrogated when IL-1Ra was added before LPS. Similar to melanoma adherence, a 2.5-fold increase (P < .05) in functional mannose receptors was observed with LPS treatment but was prevented by the addition of IL-1Ra did not affect basal mannose-receptor activity in unstimulated epithelium. Mannose-receptor activity and B16 cell adherence significantly correlated (r = .9) with LPS treatment. Conditioned medium from LPS-stimulated epithelium augmented B16 cell proliferation compared with control conditioned medium (P < .01). Production of B16 cell growth factor(s) was markedly reduced (P < .01) when IL-1Ra was added.Conclusions: These results demonstrate that systemic inflammation induces an enhancement of melanoma cell metastasis and growth by IL-1-dependent mechanisms in vivo. In vitro, the mechanism(s) is consistent with IL-1-mediated increase in expression of mannose receptors and production of tumor cell growth factor(s) from the endothelium.Implications: Given the multiple and complex cytokine cascade induced in vivo and in vitro during LPS-induced systemic inflammation, IL-1 plays a strategic role. Since IL-1Ra is without side effects in humans, studies on intraoperative infusion of IL-1Ra during tumor resection may be indicated. [ABSTRACT FROM AUTHOR]

The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cancer is first a localized tissue disorder, whose soluble and exosomal molecules and invasive cells induce a host response providing the stromal components of the primary tumor microenvironment (TME). Once the TME is developed, cancer-derived molecules and cells can more efficiently spread out and a whole-body response takes place, whose pathophysiological changes may result in a paraneoplastic syndrome. Remote organ-specific prometastatic reactions may also occur at this time, facilitating metastatic activities of circulating tumor cells (CTCs) through premetastatic niche development at targeted organs. However, additional signaling factors from the inter-organ communication network involved in the pathophysiology and comorbidities of cancer patients may also regulate prometastatic reaction-stimulating effects of cancer and non-cancer tissue factors. This article provides a conceptual overview of our ongoing clinical research on the liver prometastatic reaction (LPR) of patients with colorectal cancer (CRC), their portal vein- and hepatic artery-driven LPR-Stimulating Factors (LPR-SF), and their resulting LPR-derived Metastasis-Stimulating Factors (LPR-MSF) acting on liver-invading CRC cells. In addition, we also provide new insights on the molecular subtyping of LPR-responsive cancer phenotypes in patients with CRC and melanoma; and on how to investigate and interpret the prometastatic infrastructure in the real pathophysiological context of patients with cancer undergoing surgical procedures and receiving pharmacological treatments with multiple side effects, including those affecting the LPR, its stimulating factors and responsive cancer phenotypes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To mimic the perioperative microenvironment where bacterial products get in contact with colorectal cancer (CRC) cells and study its impact on protein release, we exposed six CRC cell lines to lipopolysaccharide (LPS) and investigated the effect on the secretome using in-depth mass spectrometry-based proteomics., Experimental Design: Cancer cell secretome was harvested in bio-duplicate after LPS treatment, and separated in EV and soluble secretome (SS) fractions. Gel-fractionated proteins were analysed by label-free nano-liquid chromatography coupled to tandem mass spectrometry. NF-κB activation, triggered upon LPS treatment, was evaluated., Results: We report a CRC secretome dataset of 5601 proteins. Comparison of all LPS-treated cells with controls revealed 37 proteins with altered abundance in the SS, including RPS25; and 13 in EVs, including HMGB1. Comparing controls and LPS-treated samples per cell line, revealed 564 significant differential proteins with fold-change >3. The LPS-induced release of RPS25 was validated by western blot., Conclusions and Clinical Relevance: Bacterial endotoxin has minor impact on the global CRC cell line secretome, yet it may alter protein release in a cell line-specific manner. This modulation might play a role in orchestrating the development of a permissive environment for CRC liver metastasis, especially through EV-communication., (© 2021 Wiley-VCH GmbH.)

Background: Metabolic syndrome (MetS) is a heterogeneous clinical entity associated with insulin resistance, low-grade proinflammatory balance and impaired endothelial function, accelerating atherosclerosis. Atherosclerotic lesions worsen with age, smoking and co-morbidities, making it difficult to accurately diagnose the cardiovascular disease (CVD) risk., Aim: We investigate the association between subclinical atherosclerosis and the presence of blood parameters related to adipocyte and vascular endothelial cell dysfunction, in non-smokers with MetS, under 60 and without previous CVD events., Methods: Seventy-eight asymptomatic individuals (average 46.5 years, 69% male; 59 MetS and 19 controls) were studied prospectively. Subclinical CVD was defined by the presence of carotid plaque and/or carotid intima-media thickness (CIMT) > 0.9 in 2/3D ultrasound-studies, left ventricular hypertrophy (LVH) or high coronary calcium score (CCS). Multiplex immunoassay by Luminex xMAP was performed to measure plasma levels of adipokines and endothelial cell-derived molecules., Results: Compared with controls, MetS patients had higher prevalence of carotid plaque (25 vs. 0%, p = 0.01), CIMT>0.9 (73 vs. 26%, p = 0.001) and higher CCS (69 vs. 5, p = 0.01), which were associated with a remarkable decrease in plasma Omentin levels and increase in sICAM-1, sVCAM-1 and PAI-1 (p <0.05). There was a statistically significant association between CIMT and sICAM-1 (OR: 14.57, 95% CI: 2.56-82.73, p <0.001), sVCAM-1 (OR:7.33, 95% CI: 1,58-33.96, p = 0.007) and PAI-1 (OR:7.80, 95% CI: 1.04-22.10, p = 0.036) in patients with carotid plaque and/or CIMT>0.9. Positive correlation between plaque volume and sICAM-1 levels was also detected (r = 0.40, p = 0.045)., Conclusions: We demonstrated that the increase of sICAM-1, sVCAM-1 and PAI-1, together with decrease of omentin-1 led to a proinflammatory imbalance pointing to the presence of subclinical atherosclerosis, and improving CVD risk stratification in non-smoking patients at early stage MetS beyond traditional scores., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs., Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined., Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006)., Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Colorectal cancer (CRC) is one of the most frequent tumor types in Western countries. Approximately 20 % of patients show metastasis at the time of diagnosis, with the liver being one of the most affected organs. Transforming growth factor-beta (TGF-β) plays a regulatory role not only in the physiology of the normal colon but also in the development of CRC and its metastatic process. In this review, we analyze the molecular mechanisms leading to TGF-β dysregulation in tumor and stroma cells and the modification of the microenvironment that fosters CRC metastasis. Recent genomic studies have identified a CRC subtype with a mesenchymal and aggressive phenotype having TGF-β as a hub gene of this signature. Consistent with these findings, the inhibition of TGF-β signaling has been shown to impair experimental CRC metastasis to the liver. Based on these and other results conducted in various tumor types, the pharmaceutical industry has developed a variety of strategies to target TGF-β. We provide up-to-date information of these therapies, which are currently in preclinical or clinical trials.

Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1 -/- mice) impaired liver colonization and increased survival of Id1 -/- animals. Histologically, the presence of Id1 in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1 +/+ mice and Id1 -/- mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Id1 significantly correlated with vimentin and other EMT-related proteins. Id1 loss decreased the levels of vimentin, integrinβ1, TGFβ1 and snail, both in vitro and in vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis., (Copyright © 2017 Elsevier B.V. All rights reserved.)