Proangiogenic Implications of Hepatic Stellate Cell Transdifferentiation into Myofibroblasts Induced by Tumor Microenvironment

Olaso, Elvira; Arteta, Beatriz; Salado, Clarisa; Eguilegor, Eider; Gallot, Natalia; Lopategi, Aritz; Gutiérrez, Virginia Franco; Solaun, Miren; Mendoza, Lorea; Vidal‐Vanaclocha, Fernando

doi:10.1007/0-387-33650-8_10

Cited by 2 publications

(3 citation statements)

References 43 publications

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“…The architecture of a malignant solid tumor consists of a mixture of cancer cells and host cells in variable proportions 23. The interactions of cancer cells with stromal cells and especially with cytokines, chemokines and growth factors derived from stromal cells, are important for the cancer development and are currently under investigation 6, 24.…”

Section: Discussionmentioning

confidence: 99%

“…Because HSCs play such an important role in HCC progression, activated HSCs may be a suitable target for HCC therapy. Importantly, targeting these stromal cells rather than the HCC cells may result in a greater response, because the stromal cells appear to have a more normal and relatively stable genetic landscape when compared to the heterogeneous and genetically unstable HCC cells 23…”

Section: Discussionmentioning

confidence: 99%

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Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice

Zhao

Zhang

Yin

et al. 2011

Intl Journal of Cancer

107

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Activated hepatic stellate cells (HSCs) play a central role in the hepatic fibrosis and cirrhosis. Recently, HSCs were reported to have strong immune modulatory activities. However, the role of HSCs in hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that HSCs could promote HCC growth both in vitro and in vivo. We examined the HSC-mediated inhibition of T-cell proliferation and the ability of conditioned medium from activated HSCs to promote the growth of murine HCC cell lines in vitro. We also assessed the immune suppression by HSCs during the development of HCC in immunocompetent mice. Cotransplantation of HSCs promoted HCC growth and progression by enhancing tumor angiogenesis and tumor cell proliferation and by creating an immunosuppressed microenvironment. Cotransplanted HSCs inhibited the lymphocyte infiltration in tumors and the spleens of mice bearing tumors, induced apoptosis of infiltrating mononuclear cells, and enhanced the expression of B7H1 and CD4 1 CD25 1 Treg cells. The immune modulation by HSCs seemed to be systemic. In conclusion, our data provide new information to support an integral role for HSCs in promoting HCC progression in part via their immune regulatory activities, and suggest that HSCs may serve as a therapeutic target in HCC.Hepatocellular carcinoma (HCC), a common malignant tumor worldwide, is a severe public health concern. 1 Carcinogenesis of HCC is a multifactor, multistep and complex process. Recently, many studies have demonstrated that hepatic fibrosis and liver cirrhosis, which are the ultimate results of chronic liver disease, are closely associated with HCC. 2 Liver fibrosis, cirrhosis and HCC all arise from liver parenchymal cells and mesenchymal cells. 3 Genetic and cellular biological studies on malignant tumors have shown that the interaction between parenchymal and stromal cells are important for tumor formation and development. 4 Stromal cells include myofibroblasts and endothelial cells, both of which interact with parenchymal cells via (1) the secretion of cytokines and other chemical factors, (2) extra cellular matrix (ECM)-mediated interaction and (3) direct cell-to-cell contiguity. 5 Stromal cells are closely related to angiogenesis, cancer desmoplasia and tumor immunity and are therefore important players in the progression, growth and spread of tumors. 6 Furthermore, several studies have shown that tumor cells can further induce the expression of tumorigenic factors in tumor-associated stromal cells, 7,8 indicating a mutual interaction between cancer cells and stromal cells. Thus, studies on the role of tumor stroma in the development and progression of cancer will help to clarify the mechanisms of carcinogenic lesions and lead to more effective therapeutic approaches.Hepatic stellate cells (HSCs) are the main collagen-producing cells in the injured liver. 9 Following a chronic liver injury, HSCs play important roles during the development of

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice

Zhao

Zhang

Yin

et al. 2011

Intl Journal of Cancer

107

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“…This phase is also supported by the intrametastatic recruitment of perisinusoidal hepatic stellate cells, portal fibroblasts and hepatocytes activated by tumor-derived factors. These cells get integrated among metastatic cancer cells forming a heterogeneous stroma that releases paracrine growth factors for cancer cells, and creates a preangiogenic stromal support [ 64 ].…”

Section: The Intralobular Micrometastasis Phasementioning

confidence: 99%

The Prometastatic Microenvironment of the Liver

Vidal‐Vanaclocha

2008

Cancer Microenvironment

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108

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The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion-and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist antitumor hepatic defense and to take advantage of hepatic cellderived factors are key phenotypic properties of livermetastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.

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Proangiogenic Implications of Hepatic Stellate Cell Transdifferentiation into Myofibroblasts Induced by Tumor Microenvironment

Cited by 2 publications

References 43 publications

Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice

Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice

The Prometastatic Microenvironment of the Liver

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