Mini-reviewPositive feedback loop between cancer stem cells and angiogenesis in hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide, as 748,300 new cases are diagnosed yearly. The incidence of HCC differs greatly depending on the geographic area and gender, with the highest prevalence of HCC occuring in East and Southeast Asia, as well as in Middle and West Africa. In addition, the incidence of HCC in men is approximately four times higher than that in women. Hepatitis B or C virus infection and alcohol-related liver damage are the major risk factors for HCC [1], [2].
HCC is a highly vascularized solid tumor with rapid growth rate and poor prognosis. At present, liver resection or transplantation is the first-line treatment for patients with HCC, however, they showed only a 50% 5-year survival rate and a 70% recurrence rate [3]. Transcatheter arterial chemoembolization (TACE), a treatment referring to injection of anticancer drugs and iodized oil into the hepatic artery and followed by the administration of embolic agents, is more effective than systemic chemotherapy or conservative treatment [4]. For recurrent and un-resectable HCC, anti-angiogenesis therapies are the clinical standard cares, and Sorafenib, a multi-kinase inhibitor of angiogenesis, has been approved for advanced HCC [5]. While the antiangiogenesis treatments definitely showedmodest efficacies and provide alternative therapies for patients with HCC, the recurrence rate and mortality have not been significantly improved [6], [7]. Recent studies have attributed these problems to the existence of cancer stem cells (CSCs) in the HCC tumor mass [8], [9], [10]. CSCs or tumor-initiating cells are a rare population of cells that drives tumor initiation and growth. They play critical roles in tumor metastasis/recurrence, and the resistance to chemotherapy/radiotherapy in various malignancies [11].
Emerging evidence in particular from breast and brain cancer studies have documented the presence of crosstalks between CSCs and angiogenesis in tumor microenvironment, and they are directly associated with cancer development, progression and metastasis [12], [13]. As one of the most vascular solid tumors, the role of angiogenesis in hepatocarcinogenesis has been investigated extensively. Because targeting against CSCs is a very promising approach for the development of curative treatments to cancer, the field of CSCs research is flourishing in recent years. Plenty of studies have also explained the biological features, functions and clinical significance of CSCs in HCC. More recently, researchers are interested in understanding the communications between CSCs and their microenvironment in HCC. However, tumor microenvironment is composed of various components and involves very complex mechanisms. As two most important pathological events in tumor microenvironment, the interactions between angiogenesis and CSCs in HCC remain elusive.
We summarized here the recent advances in these fields and proposed the presence of a feedback loop between angiogenesis and CSCs in tumor microenvironment that should play critical roles in tumor development and therapeutic resistance for HCC.
Section snippets
Angiogenesis and CSCs in HCC
Tumor angiogenesis is essential for tumor growth and metastasis in solid tumor. Angiogenesis is a multistep process that is tightly regulated by various factors in tumor microenvironment [14], [15]. There are plenty of reviews on this topic. Generally, in their early stage, the growing tumor cells can obtain nutrients from the surrounding tissue via permeation process. If a tumor lesion exceeds a few millimeters in diameter, of which the permeation process is no longer sufficient to the
Cancer stem cells in HCC
The cancer stem cells paradigm hypothesizes that tumors are frequently composed of heterogeneous cell types, in which a rare population of CSCs or tumor-initiating cells drives tumor initiation and growth, as well as tumor metastasis, recurrence, and chemotherapy/radiotherapy resistance. Therefore, therapies targeting CSCs could have major impact on cancer patient survival [11], [20], [21]. A large number of studies related to CSCs of HCC have been published in the last ten years. Many reviews
The crosstalks between angiogenesis and CSCs in HCC
A increasing number of evidence have suggested that a close communication between CSCs and angiogenesis is present in tumor microenvironment, named by “crosstalk”, which is responsible for carcinogenesis and cooperatively promotes tumor growth and therapeutic resistances. An excellent review illustrated this phenomenon in various cancers but it was rarely involved in HCC. As described below, we summarized the research progress related to the interactions between CSCs and angiogenesis in the
Antiangiogenic therapy and cancer stem cells in HCC
TACE is the first line treatment for patients with unresectable HCC due to the hypervascularization and early arterial enhancement monitored by imaging test [80], [81]. However, tumor progression and metastasis are still observed in many patients treated by TACE, due to TACE-induced hypoxia and the compensatory revascularization [82]. Consistent with these observations, increased VEGF level is observed in the peripheral blood of TACE patients, suggesting that TACE treatment activates extrinsic
Conclusions
Emerging evidence have suggested the existence of positive feedback loops consist of angiogenesis, hypoxia and CSCs in tumor microenvironment. These feedback loops play critical roles in the development of HCC and the resistance of cancer cells to angiogenic therapeutic drugs. Based on this hypothesis, we suggest that an effective anti-angiogenic therapy should also target CSCs for HCC treatment. (Fig. 1, Fig. 2)
Conflict of interest
The authors have declared no potential conflicts of interest.
Acknowledgments
This work was supported by grants from National Natural Science Foundations of China (Grants Nos. 81372460 and 81272549) and Jiansu Key Project for Natural Science Research of University (Grants Nos. 11KJA320002 and 14KJA320003).
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2022, Seminars in Cancer BiologyCitation Excerpt :Such positive feedback loops could perpetuate the stage of a program involving proliferation, which therefore blocks the transition from this stage of the program to next stage [328,329]. Such positive feedback loops are described between cancer cells and the extracellular matrix [110–112], between cancer cells and cancer-associated fibroblasts [77,330,331], between cancer cells and macrophages [332,333], between inflammatory processes of the bone cancer cells [334], between cancer stem-like cells and tumor-associated neutrophils [335], between cancer stem cells and angiogenesis [336], between WNT5A and interleukin-6 [140], between NOTCH1-SOX2 [337], between Wnt/β-catenin and VASP [338], between ADAM12 and FAK [339], between Treg cells and type 2-skewed macrophages [141], and between ZEB1/HAS2 [340], among others. Therefore, the specific microenvironment of malignancy supports not only sustained division and matrix stiffening but also other pro-malignant mechanisms, such as positive feedback loops.
Exosome-derived noncoding RNAs: Function, mechanism, and application in tumor angiogenesis
2022, Molecular Therapy Nucleic AcidsCitation Excerpt :The overexpression of exosome-derived miR-16 and miR-100 from MSCs downregulates the expression of VEGF in breast cancer cells, thereby inhibiting angiogenesis and tumor growth in vivo and in vitro.80,82 CSCs are regarded as the basic cells in heterogeneous tumor tissue, and their secreted exosomes become effective TME regulators that affect tumor angiogenesis, especially the self-renewing regulatory ncRNAs they carry, which play a key role.83 Exosomes secreted by CD90+ hepatoma cells, which are defined as CSCs, upregulate VEGF by passing overexpressed lncRNAH19 to ECs to promote angiogenesis and tumor growth.84