Mechanical stiffness of liver tissues in relation to integrin β1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma

Zhao, Gang; Cui, Jing; Qi, Qin; Zhang, Jungang; Liu, Lin; Deng, Shichang; Wu, Chunrui; Yang, Ming; Li, Shaoshan; Wang, Chunyou

doi:10.1002/jso.21613

Cited by 66 publications

(59 citation statements)

References 33 publications

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“…Hypoxia, inflammation and liver stiffness are the most remarkable features of HCC microenvironment. Any of these stimuli can partially influence or determine the development and progression of HCC, and be associated with clinical outcomes closely [15, 16, 48–53]. Accumulating evidences illustrate that hypoxia and several inflammation cytokines regulate the stemness properties of HCC cells [54–56].…”

Section: Discussionmentioning

confidence: 99%

“…Some literatures on HCC study indicate that matrix stiffness regulating HCC cell proliferation, drug resistance and angiogenesis might be through focal adhesion kinase (FAK), extracellular-signal-regulated kinase (ERK) /signal transducer and activator of transcription member 3 (STAT3), c-Jun N-terminal kinase (JNK), and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathways [12–14]. Other studies demonstrate that the mechanical stiffness of ECM remarkably correlates with HCC invasion and metastasis via controlling the expression of integrin β1 [15], and lysyl oxidase 2-mediated tissue stiffness increase promotes intrahepatic metastasis of HCC [16]. In addition, higher matrix stiffness also upregulates osteopontin (OPN) expression in HCC cells by activating integrin β1/GSK3β/β-catenin signaling pathway [17], and forces the expression of vascular endothelial growth factor through integrin β1/AKT/PI3K signaling pathway [14], thereby suggesting that it may participate in the regulation of the expression levels of some invasion/metastasis-associated genes and ultimately influence HCC metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

et al. 2016

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Matrix stiffness as an important physical attribute of extracellular matrix exerts significant impacts on biological behaviors of cancer cells such as growth, proliferation, motility, metabolism and invasion. However, its influence on cancer stemness still remains elusive. Here, we explore whether matrix stiffness-mediated effects on stemness characteristics occur in HCC cells. As the substrate stiffness increased, HCC cells exhibited high proportion of cells with CD133(+)/EpCAM(+), high expression levels of CD133, EpCAM, Nanog and SOX2, greater self-renewing ability and oxaliplatin resistance. Simultaneously, their phosphorylation levels of Akt and mTOR, as well as p-4E-BP and SOX2 expressions were also obviously upregulated. Conversely, knockdown of integrin β1 partially attenuated higher stiffness-mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin β1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway. Additionally, mTOR inhibitor suppressed the mTOR phosphorylation level and expression levels of p-4E-BP and SOX2 in HCC cells grown on higher stiffness substrate, as well as depressed their stemness properties significantly, favoring a regulating role of mTOR signaling pathway in matrix stiffness-mediated effects on stemness. In summary, matrix stiffness may be involved in the process of stemness regulation via activating integrin β1/Akt/mTOR/SOX2 signaling pathway. To the best of our knowledge, this study first reveals a novel regulating pathway to direct the stemness characteristics in HCC cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

et al. 2016

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“…For example, hepatocellular death results in mice with hepatocyte-specific deletion of integrin-linked kinase, suggesting a key role of this pathway in linking the ECM to epithelial cell survival (115). Accordingly, there is an increase in integrin expression within tumors in different mouse models of HCC (76), as well as increased expression of integrin α6 and integrin β1 in HCC samples from patients (116, 117). Moreover, integrin expression correlates with pathologic grade, tumor encapsulation, and outcomes (116, 117).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

“…Accordingly, there is an increase in integrin expression within tumors in different mouse models of HCC (76), as well as increased expression of integrin α6 and integrin β1 in HCC samples from patients (116, 117). Moreover, integrin expression correlates with pathologic grade, tumor encapsulation, and outcomes (116, 117). SNPs in integrin αV influence HCC growth in patients (118).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Affò

Schwabe

2017

Annu. Rev. Pathol. Mech. Dis.

502

425

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Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix—associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.

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“…75 Increased tissue stiffness has also been correlated with liver, pancreatic, and prostate cancer. 33,48,49,69,113 Matrix stiffness contributes significantly to cancer progression, and these findings are just one part of a growing body of evidence that all cells are highly responsive to the mechanical properties of their surroundings. 26 The fluid environment of the tumor and stroma also experiences dramatic changes as the tumor grows.…”

Section: Biomechanics Of the Tumor Microenvironmentmentioning

confidence: 99%

Biomechanical Forces Shape the Tumor Microenvironment

2011

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The importance of the tumor microenvironment in cancer progression is indisputable, yet a key component of the microenvironment--biomechanical forces--remains poorly understood. Tumor growth and progression is paralleled by a host of physical changes in the tumor microenvironment, such as growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow. These changes to the biomechanical microenvironment promote tumorigenesis and tumor cell invasion and induce stromal cells--such as fibroblasts, immune cells, and endothelial cells--to change behavior and support cancer progression. This review highlights what we currently know about the biomechanical forces generated in the tumor microenvironment, how they arise, and how these forces can dramatically influence cell behavior, drawing not only upon studies directly related to cancer and tumor cells, but also work in other fields that have shown the effects of these types of mechanical forces vis-à-vis cell behaviors relevant to the tumor microenvironment. By understanding how all of these biomechanical forces can affect tumor cells, stromal cells, and tumor-stromal crosstalk, as well as alter how tumor and stromal cells perceive other extracellular signals in the tumor microenvironment, we can develop new approaches for diagnosis, prognosis, and ultimately treatment of cancer.

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Mechanical stiffness of liver tissues in relation to integrin β1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma

Abstract: Expression of integrin β1 is regulated by the mechanical stiffness of the ECM, and correlates with the invasion and metastasis events of HCC in patients with cirrhosis.

Cited by 66 publications

References 33 publications

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Biomechanical Forces Shape the Tumor Microenvironment

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