Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells <i>In Vivo</i>

Cecil, Denise L.; Slota, Meredith; O’Meara, Megan M.; Curtis, Benjamin; Gad, Ekram; Dang, Yushe; Herendeen, Daniel R.; Rastetter, Lauren; Disis, Mary L.

doi:10.1158/1078-0432.ccr-16-1678

Cited by 31 publications

(27 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, anti-tumor effects of autophagy inhibitors such as CQ is likely to be because of the inhibition of chemotherapy-induced autophagy while anti-tumor effects of autophagy inducers such as rapamycin may result from enhanced cell-intrinsic autophagy [ 9 , 10 ]. It has been reported cancer stem cells play a role in tumor dormancy [ 11 ] and drug resistance [ 12 ], and that immunotherapeutic targeting of breast cancer stem cells inhibits growth of mammary carcinoma [ 13 ]. However, we did not detect the enrichment of CD44+CD24- cancer stem cells following ADR-induced tumor dormancy (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

et al. 2018

View full text Add to dashboard Cite

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.

show abstract

Section: Discussionmentioning

confidence: 99%

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In TNBCs, overexpression of HIF-1α was associated with poor outcome in early stage disease [7] . In a recent study, immunization against HIF-1α inhibited the growth of basal mammary tumors [8] . The same study showed elevation of HIF-1α-specific IgG in TNBC patients.…”

Section: Introductionmentioning

confidence: 98%

Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts

et al. 2018

View full text Add to dashboard Cite

Hypoxia inducible factors (HIFs) are transcription factors that mediate the response of cells to hypoxia. HIFs have wide-ranging effects on metabolism, the tumor microenvironment (TME) and the extracellular matrix (ECM). Here we investigated the silencing effects of two of the three known isoforms, HIF-1α and HIF-2α, on collagen 1 (Col1) fibers, which form a major component of the ECM of tumors. Using a loss-of-function approach for HIF-1α or 2α or both HIF-1α and 2α, we identified a relationship between HIFs and Col1 fibers in MDA-MB-231 tumors. Tumors derived from MDA-MB-231 cells with HIF-1α or 2α or both HIF-1α and 2α silenced contained higher percent fiber volume and lower inter-fiber distance compared to tumors derived from empty vector MDA-MB-231 cells. Depending upon the type of silencing, we observed changes in Col1 degrading enzymes, and enzymes involved in Col1 synthesis and deposition. Additionally, a reduction in lysyl oxidase protein expression in HIF-down-regulated tumors suggests that more non-cross-linked fibers were present. Collectively these results identify the role of HIFs in modifying the ECM and the TME and provide new insights into the effects of hypoxia on the tumor ECM.

show abstract

“…Hypoxia induces nuclear factor-κB (NF-κB) and HIF-1α successively, leading to the infiltration of M2 macrophages in the tumor microenvironment and tumorigenesis (110). As compared with normal cells, triple-negative breast cancer cells have more HIF-1α-specific IgG, which indicates that HIF-1α is immunogenic (111). Treatment using a HIF-1α vaccine recruits type I T cells to the tumor tissue and effectively inhibits basal-like breast CSCs, which can inhibit tumor metastasis (111).…”

Section: Role Of Hif-1 In Tumor Immunity Of Cscsmentioning

confidence: 99%

“…As compared with normal cells, triple-negative breast cancer cells have more HIF-1α-specific IgG, which indicates that HIF-1α is immunogenic (111). Treatment using a HIF-1α vaccine recruits type I T cells to the tumor tissue and effectively inhibits basal-like breast CSCs, which can inhibit tumor metastasis (111). In order to adapt to chronic hypoxia, CD8 + T cells increase the expression of active HIF-1α and increase their own effector functions (112).…”

Section: Role Of Hif-1 In Tumor Immunity Of Cscsmentioning

confidence: 99%

“…The targeted inhibition of HIF-1 by siRNA can increase the radiotherapy sensitivity of malignant gliomas, but the limited delivery efficiency of siRNA still needs to be resolved (153,154). The HIF-1α vaccine is proposed to inhibit breast cancer metastasis from the perspective of tumor immunity (111). Not only that, the combination of HIF-1α and co-activators can also become a potential therapeutic target.…”

Section: Potential Targets For Csc Therapymentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

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

show abstract

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

Cited by 31 publications

References 38 publications

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts

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

Contact Info

Product

Resources

About