| 1. |
- Latacz, Emily, et al.
(author)
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Histopathological growth patterns of liver metastasis : updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights
- 2022
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In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 127:6, s. 988-1013
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Research review (peer-reviewed)abstract
- 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.
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| 2. |
- Siegel, Peter M., et al.
(author)
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The tumor microenvironment of colorectal cancer liver metastases : molecular mediators and future therapeutic targets
- 2022
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In: Contemporary management of metastatic colorectal cancer. - : Elsevier. - 9780323917063 - 9780323985680 ; , s. 17-44
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Book chapter (peer-reviewed)abstract
- The liver has evolved to maintain tissue homeostasis and a state of immune-unresponsiveness in the face of constant exposure to food-derived and commensal microbial products entering through the portal circulation. This is achieved by the unique properties of cells residing in the liver that function to dampen adaptive immune responses. Here we will survey the unique features of the liver microenvironment that contribute to this general state of immune-tolerance and render the liver particularly “hospitable” to incoming metastatic cancer cells. The diverse cell types and unique liver ECM, which collectively control the progression of metastasis and can act to curtail or promote the process, will be described and recent insight into their respective roles highlighted.
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| 3. |
- van Dam, Pieter-Jan, et al.
(author)
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International consensus guidelines for scoring the histopathological growth patterns of liver metastasis
- 2017
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In: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 117:10, s. 1427-1441
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Vaniotis, George, et al.
(author)
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Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis
- 2018
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In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 37:28, s. 3790-3805
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Journal article (peer-reviewed)abstract
- Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27colIV) cells increased their metastatic ability, specifically to the liver and documented high collagen IV levels in surgical resections of liver metastases from diverse tumor types. Here, we aimed to elucidate the functional relevance of collagen IV to metastatic outgrowth in the liver. Gene expression profiling revealed in M27colIVcells significant increases in the expression of chemokines CCL5 (5.7-fold) and CCL7 (2.6-fold) relative to wild-type cells, and this was validated by qPCR and western blotting. Similarly, in human colon carcinoma KM12C and KM12SM cells with divergent liver-colonizing potentials, CCL7 and CCL5 production correlated with type IV collagen expression and the metastatic phenotype. CCL7 silencing by short hairpin RNA (shRNA) reduced experimental liver metastasis in both cell types, whereas CCL5 silencing reduced metastasis of M27colIV cells, implicating these cytokines in metastatic expansion in the liver. Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3. Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver. Loss of CCL7 in KM12SM cells was also associated with altered E-cadherin and reduced vimentin and Snail expression, implicating it in epithelial-to-mesenchymal transition in these cells. Moreover, in clinical specimens of colon cancer liver metastases analyzed by immunohistochemistry, CCL5 and CCL7 levels paralleled those of collagen IV. The results identify the chemokines CCL5 and CCL7 as type IV collagen-regulated genes that promote liver metastasis by distinct and complementary mechanisms.
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