Myofibroblasts Derived from Hepatic Progenitor Cells Create the Tumor Microenvironment

Sekiya, Sayaka; Miura, Shizuka; Matsuda-Ito, Kanae; Suzuki, Atsushi

doi:10.1016/j.stemcr.2016.11.002

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…Moreover, growth factors and chemokines produced by cancer and endothelial cells promote stromal fibroblast activation, infiltration of T lymphocytes, macrophage activation and fibroblasts differentiation into myofibroblasts and cancer associated fibroblasts (CAFs) [28]. Myofibroblasts and CAFs, found in the stroma of carcinomas and especially in the tumor invasive edge, secrete ECM proteins, cytokines, growth factors, chemokines, hormones and inflammation proteins, thus promoting cancer cell proliferation and CSCs de-differentiation and migration [29,30]. The main contribution of CAFs and myofibroblasts to tumor microenvironment is therefore the synthesis and release of significant amounts of ECM proteins; newly deposited collagen and elastin fibers, in fact, are reoriented and remodeled to generate larger, more-rigid fibrils that contribute to the tumor-surrounding ECM special features [31,32].…”

Section: The Tumor Microenvironment and Ecm Modificationsmentioning

confidence: 99%

Extracellular Matrix Alterations in Metastatic Processes

Paolillo

Schinelli

2019

IJMS

287

191

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The extracellular matrix (ECM) is a complex network of extracellular-secreted macromolecules, such as collagen, enzymes and glycoproteins, whose main functions deal with structural scaffolding and biochemical support of cells and tissues. ECM homeostasis is essential for organ development and functioning under physiological conditions, while its sustained modification or dysregulation can result in pathological conditions. During cancer progression, epithelial tumor cells may undergo epithelial-to-mesenchymal transition (EMT), a morphological and functional remodeling, that deeply alters tumor cell features, leading to loss of epithelial markers (i.e., E-cadherin), changes in cell polarity and intercellular junctions and increase of mesenchymal markers (i.e., N-cadherin, fibronectin and vimentin). This process enhances cancer cell detachment from the original tumor mass and invasiveness, which are necessary for metastasis onset, thus allowing cancer cells to enter the bloodstream or lymphatic flow and colonize distant sites. The mechanisms that lead to development of metastases in specific sites are still largely obscure but modifications occurring in target tissue ECM are being intensively studied. Matrix metalloproteases and several adhesion receptors, among which integrins play a key role, are involved in metastasis-linked ECM modifications. In addition, cells involved in the metastatic niche formation, like cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM), have been found to play crucial roles in ECM alterations aimed at promoting cancer cells adhesion and growth. In this review we focus on molecular mechanisms of ECM modifications occurring during cancer progression and metastatic dissemination to distant sites, with special attention to lung, liver and bone. Moreover, the functional role of cells forming the tumor niche will also be reviewed in light of the most recent findings.

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Section: The Tumor Microenvironment and Ecm Modificationsmentioning

confidence: 99%

Extracellular Matrix Alterations in Metastatic Processes

Paolillo

Schinelli

2019

IJMS

287

191

View full text Add to dashboard Cite

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“…In a recent study, Sekiya et al have shown that HPCs isolated from mice injured liver can differentiate into myofibroblasts, as a third distinct cell type, in addition to hepatocyte and cholangiocyte differentiation. They also have proposed that HPCs can contribute to the formation of the premalignant niche by abundant production of myofibroblasts [35].…”

Section: Fibrocytesmentioning

confidence: 99%

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)-and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

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“…32 Previous reports have also shown that HPCs can serve as a source of MFs that may create a microenvironment for tumour development arising through the progression of chronic liver injury. 33 Our in vivo and in vitro experiments showed that HPCs differentiate into MFs via the action of LPS. Meanwhile, hepatobiliary differentiation was inhibited, indicating that HPCs aggravate liver fibrosis due to their abnormal differentiation into MFs under the influence of LPS.…”

Section: Discussionmentioning

confidence: 75%

Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts via activation of the Hedgehog signaling pathway

et al. 2017

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Normally, hepatic progenitor cells (HPCs) are activated and differentiate into hepatocytes or bile ductular cells to repair liver damage during liver injury. However, it remains controversial whether the abnormal differentiation of HPCs occurs under abnormal conditions. Lipopolysaccharide (LPS), a component of the microenvironment, promotes liver fibrosis. In the present study, HPCs promoted liver fibrosis in rats following carbon tetrachloride (CCl) treatment. Meanwhile, the LPS level in the portal vein was elevated and played a primary role in the fate of HPCs. In vitro, LPS inhibited the hepatobiliary differentiation of HPCs. Concurrently, HPCs co-cultured with LPS for 2 weeks showed a tendency to differentiate into myofibroblasts (MFs). Thus, we conclude that LPS promotes the aberrant differentiation of HPCs into MFs as a third type of descendant. This study provides insight into a novel differentiation fate of HPCs in their microenvironment, and could thus lead to the development of HPCs for treatment methods in liver fibrosis.

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Myofibroblasts Derived from Hepatic Progenitor Cells Create the Tumor Microenvironment

Cited by 11 publications

References 34 publications

Extracellular Matrix Alterations in Metastatic Processes

Extracellular Matrix Alterations in Metastatic Processes

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts via activation of the Hedgehog signaling pathway

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