Identification of Target PTEN-Based miR-425 and miR-576 as Potential Diagnostic and Immunotherapeutic Biomarkers of Colorectal Cancer With Liver Metastasis

A major complication of colorectal cancer (CRC), one of the most common and fatal types of cancers, is secondary liver metastasis. For patients with this fate, there are very few biomarkers available in clinical application, and the disease remains incurable. Recently, increasing studies demonstrated that tumorigenesis and development are closely related to immune escape, indicating that the roles of immune-related indicators might have been neglected in the past in colorectal cancer liver metastases (CRLM). Here, we unveil that elevated miR-425 and miR-576 promote CRLM through inhibiting PTEN-mediated cellular immune function. Specifically, miR-425 and miR-576 were identified for their significant upregulation in CRLM compared with the primary CRC tissues based on GSE81581 (n = 8) and GSE44121 (n = 18) datasets. Besides, we determined that the two microRNAs (miRNAs) coparticipated in restraining P53 and transforming growth factor beta (TGF-β) signaling pathways associated with tumor metastasis, and both shortened the overall survival of the patients with metastatic susceptibility. Notably, in situ hybridization on relatively large samples of paired CRC tissues (n = 157) not only substantiated that the expression of miR-425 and miR-576 was dramatically upregulated in CRLM but also revealed that they were closely related to tumor deterioration, especially liver metastases. Moreover, we further confirmed that the combination of miR-425 and miR-576 was an effective predictive model for liver metastases and poor clinical outcomes. Mechanically, downregulated PTEN (GSE81558, n = 6) was verified to be a shared target of miR-425 and miR-576 acting as metastasis-related oncogenes, on account of the presence of binding sites (+2928–+2934 and +4371–+4378, respectively) and the collaborative suppression of P53/TGF-β signaling in CRLM, which was further confirmed in CRC cells (HCT116 and SW480) based on systematic molecular biology experiments. Importantly, the target PTEN was strongly associated with microsatellite instability, tumor microenvironment, and immune cell infiltration. Thus, we speculate that miR-425 and miR-576 are novel biomarkers for CRLM prevention and immunotherapy and upstream inhibitors of the PTEN-P53/TGF-β function axis.

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Histologically Verified Biliary Invasion was Associated with Impaired Liver Recurrence-Free Survival in Resected Colorectal Cancer Liver Metastases

Scandinavian Journal of Surgery ◽

10.1177/1457496918812237 ◽

2018 ◽

Vol 108 (3) ◽

pp. 201-209 ◽

Cited By ~ 2

Author(s):

P. Reijonen ◽

P. Österlund ◽

H. Isoniemi ◽

J. Arola ◽

A. Nordin

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Liver Metastasis ◽

Liver Metastases ◽

Recurrence Free Survival ◽

Colorectal Cancer Liver Metastases ◽

Free Survival ◽

Colorectal Cancer Liver Metastasis ◽

Liver Recurrence ◽

Disease Free

Background and Aims: The impact of biliary invasion on recurrence and survival, after resection of colorectal cancer liver metastases, is not well known as publications are limited to small patient series. The aim was to investigate if biliary invasion in liver resected patients associated with liver relapses and recurrence-free survival. Secondary endpoints included association with other prognostic factors, disease-free survival and overall survival. Materials and Methods: All patients with histologically verified biliary invasion (n = 31, 9%) were identified among 344 patients with liver resection between January 2009 and March 2015. Controls (n = 78) were selected from the same time period and matched for, among others, size and number of colorectal cancer liver metastasis. Results: Median liver recurrence-free survival was significantly shorter in patients with biliary invasion than in controls (15.3 months versus not reached; p = 0.031) and more relapses were noted in the liver (61.3% versus 33.3%; p = 0.010), respectively. In univariate analyses for liver recurrence-free survival, biliary invasion was the only significant prognostic factor; p = 0.034. There were no statistical differences in disease-free and overall survival between the groups. Conclusion: Biliary invasion was associated with higher liver recurrence rates and shorter liver recurrence-free survival in patients with resected colorectal cancer liver metastasis.

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Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

Communications Biology ◽

10.1038/s42003-021-02189-9 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Sébastien Tabariès ◽

Matthew G. Annis ◽

Anthoula Lazaris ◽

Stephanie K. Petrillo ◽

Jennifer Huxham ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Growth Pattern ◽

Treatment Strategies ◽

Immunohistochemical Analysis ◽

Colorectal Cancer Liver Metastases ◽

Colorectal Cancer Liver Metastasis ◽

Breast Cancer Liver Metastasis ◽

Colorectal Cancer Patients

AbstractClaudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.

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Radiomics and Radiogenomics in Evaluation of Colorectal Cancer Liver Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2021.689509 ◽

2022 ◽

Vol 11 ◽

Author(s):

Yun Wang ◽

Lu-Yao Ma ◽

Xiao-Ping Yin ◽

Bu-Lang Gao

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Texture Features ◽

Biological Properties ◽

Imaging Features ◽

Current Application ◽

Colorectal Cancer Liver Metastases ◽

Colorectal Cancer Liver Metastasis ◽

Non Invasive

Colorectal cancer is one common digestive malignancy, and the most common approach of blood metastasis of colorectal cancer is through the portal vein system to the liver. Early detection and treatment of liver metastasis is the key to improving the prognosis of the patients. Radiomics and radiogenomics use non-invasive methods to evaluate the biological properties of tumors by deeply mining the texture features of images and quantifying the heterogeneity of metastatic tumors. Radiomics and radiogenomics have been applied widely in the detection, treatment, and prognostic evaluation of colorectal cancer liver metastases. Based on the imaging features of the liver, this paper reviews the current application of radiomics and radiogenomics in the diagnosis, treatment, monitor of disease progression, and prognosis of patients with colorectal cancer liver metastases.

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Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

Communications Biology ◽

10.1038/s42003-021-02481-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Miran Rada ◽

Audrey Kapelanski-Lamoureux ◽

Stephanie Petrillo ◽

Sébastien Tabariès ◽

Peter Siegel ◽

...

Keyword(s):

Colorectal Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Growth Patterns ◽

Colorectal Cancer Liver Metastases ◽

Related Transcription Factor ◽

Transcription Factor 1

AbstractColorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFβ1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.

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Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.612774 ◽

2021 ◽

Vol 9 ◽

Author(s):

Gwendolyn Haas ◽

Shuang Fan ◽

Michael Ghadimi ◽

Tiago De Oliveira ◽

Lena-Christin Conradi

Keyword(s):

Colorectal Cancer ◽

Cancer Therapy ◽

Liver Metastases ◽

Blood Supply ◽

Immune Cell ◽

Therapeutic Option ◽

Alternative Mechanism ◽

Colorectal Cancer Liver Metastases ◽

Sprouting Angiogenesis ◽

Anti Cancer

In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.

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Whole exome and transcriptome sequencing reveal clonal evolution and exhibit immune-related features in metastatic colorectal tumors

Cell Death Discovery ◽

10.1038/s41420-021-00607-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chunxue Li ◽

Juan Xu ◽

Xiangfeng Wang ◽

Chao Zhang ◽

Zicheng Yu ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Colorectal Liver Metastasis ◽

Immune Cell ◽

Immune Escape ◽

Clonal Evolution ◽

Copy Number Variations ◽

Tumor Evolution ◽

Whole Exome ◽

Recurrent Mutations

AbstractLiver is the most common site where metastatic lesions of colorectal cancer (CRC) arise. Although researches have shown mutations in driver genes, copy number variations (CNV) and alterations in relevant signaling pathways promoted the tumor evolution and immune escape during colorectal liver metastasis (CLM), the underlying mechanism remains largely elusive. Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during CLM. Shared somatic mutations between primary and metastatic tissues with a commonly observed subclonal-clonal (S-C) changing pattern indicated a common clonal origin between two lesions. The recurrent mutations with S-C changing pattern included those in KRAS, SYNE1, CACNA1H, PCLO, FBXL2, and DNAH11. The main CNV events underwent clonal-clonal evolution (20q amplification (amp), 17p deletion (del), 18q del and 8p del), subclonal-clonal evolution (8q amp, 13q amp, 8p del) and metastasis-specific evolution (8q amp) during the process of CLM. In addition, we revealed a potential mechanism of tumor cell immune escape by analyzing human leukocytes antigens (HLA) related clonal neoantigens and immune cell components in CLM. Our study proposed a novel liver metastasis-related evolutionary process in colorectal cancer and emphasized the theory of neo-immune escape in colorectal liver metastasis.

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