Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells

Hajizadeh, Farnaz; Okoye, Isobel; Esmaily, Maryam; Chaleshtari, Mitra Ghasemi; Masjedi, Ali; Azizi, Gholamreza; Irandoust, Mahzad; Ghalamfarsa, Ghasem; Jadidi‐Niaragh, Farhad

doi:10.1016/j.lfs.2019.116952

Cited by 79 publications

(70 citation statements)

References 129 publications

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“…The data has indicated that HIF-1α can induce the production of multiple stem cell markers, such as OCT4, SOX2, NANOG and Krüppel-like factor 4 (KLF4) (44,79,80). In addition, the silencing of HIF-1α can hinder the progression of cancer by inhibiting the expression of stem cell markers (81). HIF-1 was found to bind directly to the CD47 promoter to facilitate gene transcription, which helps to escape phagocytosis of macrophages and maintain the stem phenotype of breast CSCs (7,82).…”

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

“…Endogenous HIF-1α is recruited to the promoter of CD24, which promotes CD24 expression, as well as tumor formation and metastasis (83). HIF-1α appears to bind to the CD133 promoter and promote the production of CD133 + glioblastoma, and colon and pancreatic CSCs via OCT4 and SOX2 (81,(84)(85)(86)(87). In addition, a correlation has been found between HIF-1α and CD133 in the cytoplasm, rather than other parts of the cell, such as the gland cavity (88).…”

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

“…Surprisingly, OCT4 isoform OCT4B in cervical cancer cells promotes neovascularization by upregulating HIF-1α production (91). The subtype of aldehyde dehydrogenase, 4-trimethylaminobutyraldehyde dehydrogenase (ALDH1A1), which is associated with the self-renewal, metastasis and resistance of cancer cells, is regulated by HIF-1α in breast cancer (81). In turn, ALDH1A1 promotes HIF-1α expression via retinoic acid signaling (81,92).…”

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

“…The subtype of aldehyde dehydrogenase, 4-trimethylaminobutyraldehyde dehydrogenase (ALDH1A1), which is associated with the self-renewal, metastasis and resistance of cancer cells, is regulated by HIF-1α in breast cancer (81). In turn, ALDH1A1 promotes HIF-1α expression via retinoic acid signaling (81,92). In addition to promoting the production of mesenchymal or EMT marker proteins, HIF-1α also inhibits the expression of epithelial marker proteins, which can be confirmed by the use of HIF-1α inhibitors (93)(94)(95).…”

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

“…HIF-1 is regulated by multiple signaling pathways in CSCs and also participates in regulating the characteristics of CSCs through signaling pathways, such as the Notch, MAPK/ERK and Wnt signaling pathways (81). Studies have found that the PI3K/Akt/mTOR pathway maintains the transcription, translation and biological activity of HIF-1α (54,124).…”

Section: Role Of Hif-1 In Signaling Pathways Associated With Cscsmentioning

confidence: 99%

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Role of hypoxia inducible factor-1 in cancer stem cells (Review)

et al. 2020

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Cancer stem cells (CSCs) have been found to play a decisive role in cancer recurrence, metastasis, and chemo-, radio-and immuno-resistance. Understanding the mechanism of CSC self-renewal and proliferation may help overcome the limitations of clinical treatment. The microenvironment of tumor growth consists of a lack of oxygen, and hypoxia has been confirmed to induce cancer cell invasion, metastasis and epithelial-mesenchymal transition, and is usually associated with poor prognosis and low survival rates. Hypoxia inducible factor-1 (HIF-1) can be stably expressed under hypoxia and act as an important molecule to regulate the development of CSCs, but the specific mechanism remains unclear. The present review attempted to explain the role of HIF-1 in the generation and maintenance of CSCs from the perspective of epigenetics, metabolic reprogramming, tumor immunity, CSC markers, non-coding RNA and signaling pathways associated with HIF-1, in order to provide novel targets with HIF-1 as the core for clinical treatment, and extend the life of patients. Contents 1. Introduction 2. Structural characteristics of HIF-1 3. Role of epigenetic and post-translational modification of HIF-1 in CSCs 4. Role of HIF-1 in non-coding RNA associated with CSCs 5. Role of HIF-1 in CSC markers 6. Role of HIF-1 in tumor immunity of CSCs 7. Role of HIF-1 in metabolic reprogramming of CSCs 8. Role of HIF-1 in signaling pathways associated with CSCs 9. Potential targets for CSC therapy 10. Conclusions and perspectives

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Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

Section: Role Of Hif-1 In Csc Markersmentioning

confidence: 99%

Section: Role Of Hif-1 In Signaling Pathways Associated With Cscsmentioning

confidence: 99%

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Role of hypoxia inducible factor-1 in cancer stem cells (Review)

et al. 2020

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Concomitant blockade of A2AR and CTLA‐4 by siRNA‐loaded polyethylene glycol‐chitosan‐alginate nanoparticles synergistically enhances antitumor T‐cell responses

Ghasemi-Chaleshtari

Kiaie

Irandoust

et al. 2020

Journal Cellular Physiology

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Inhibitory immune checkpoint (ICP) molecules are important immunosuppressive factors in a tumor microenvironment (TME). They can robustly suppress T‐cell‐mediated antitumor immune responses leading to cancer progression. Among the checkpoint molecules, cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4) is one of the critical inhibitors of anticancer T‐cell responses. Besides, the expression of adenosine receptor (A2AR) on tumor‐infiltrating T cells potently reduces their function. We hypothesized that concomitant silencing of these molecules in T cells might lead to enhanced antitumor responses. To examine this assumption, we purified T cells from the tumor, spleen, and local lymph nodes of CT26 colon cancer‐bearing mice and suppressed the expression of A2AR and CTLA‐4 using the small interfering RNA (siRNA)‐loaded polyethylene glycol‐chitosan‐alginate (PCA) nanoparticles. The appropriate physicochemical properties of the produced nanoparticles (NPs; size of 72 nm, polydispersive index [PDI] < 0.2, and zeta potential of 11 mV) resulted in their high efficiency in transfection and suppression of target gene expression. Following the silencing of checkpoint molecules, various T‐cell functions, including proliferation, apoptosis, cytokine secretion, differentiation, and cytotoxicity were analyzed, ex vivo. The results showed that the generated nanoparticles had optimal physicochemical characteristics and significantly suppressed the expression of target molecules in T cells. Moreover, a concomitant blockade of A2AR and CTLA‐4 in T cells could synergistically enhance antitumor responses through the downregulation of PKA, SHP2, and PP2Aα signaling pathways. Therefore, this combination therapy can be considered as a novel promising anticancer therapeutic strategy, which should be further investigated in subsequent studies.

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Retinoblastoma cell-derived Twist protein promotes regulatory T cell development

Zhang

Song

Duo

et al. 2020

Cancer Immunol Immunother

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Background The development of tumor tissue-infiltrating regulatory T cell (Treg) is incompletely understood. This study investigates the role of retinoblastoma cell (Rbc)-derived Twist-related protein 1 (Twist) in the Treg development. Methods The surgically removed Rb tissues were collected. Rbcs were cultured with CD4 + T cells to assess the role of Rbc-derived Twist in the Treg generation. Results We found that more than 90% Rbcs expressed Twist. Foxp3 + Tregs were detected in the Rb tissues that were positively correlated with the Twist expression in Rbcs, negatively associated with Rb patient survival and sight survival. Treating Rbcs with hypoxia promoted the Twist expression that could be detected in the cytoplasm, nuclei and on the cell surface. Twist activated CD4 + T cells by binding the TLR4/myeloid differentiation factor 2 complex and promoted the transforming growth factor-β-inducible early gene 1 product and Foxp3 expression. These Rbc-induced Foxp3 + Tregs showed immunesuppressive function on CD8 + T cell proliferation. Conclusions Rbcs express Twist, that induces IL-4 + Foxp3 + Tregs; the latter can inhibit CD8 + cytotoxic T cell activities. Therefore, Twist may play an important role in the pathogenesis of Rb.

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Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells

Cited by 79 publications

References 129 publications

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

Concomitant blockade of A2AR and CTLA‐4 by siRNA‐loaded polyethylene glycol‐chitosan‐alginate nanoparticles synergistically enhances antitumor T‐cell responses

Retinoblastoma cell-derived Twist protein promotes regulatory T cell development

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