Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer

Benefiting from treating diseases at the genetic level, gene therapy has been considered a new revolution in the biomedical field. However, the extracellular and intracellular barriers during gene transport such as enzymatic degradation and endo-/lysosomal sequestration significantly compromise the therapeutic efficacy. Though photochemical internalization (PCI) has emerged as a promising approach for causing endo-/lysosomal leakage with translocation of the internalized molecules into the cytosol, its effect is still unsatisfactory due to the insufficient light penetration depth. Here, we develop tumor microenvironment-specific enhanced gene delivery by means of ROS generated from the in situ cascaded catalytic reactions in tumors involving GOx-mediated redox reaction and Mn2+-mediated Fenton-like reaction. The efficient enzymatic protection and successful endo-/lysosomal escape of cargo gene complexes have been demonstrated. Moreover, anti-Twist siRNA-loaded G@MMSNs-P exhibit tumor-specific biodegradation, excellent T1-weighted MR imaging, and significant inhibitory effects against breast cancer growth and pulmonary metastasis.

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cPLA2 Blockade Attenuates S100A7-Mediated Breast Tumorigenicity by Inhibiting the Immunosuppressive Tumor Microenvironment

10.21203/rs.3.rs-829313/v1 ◽

2021 ◽

Author(s):

SANJAY MISHRA ◽

Manish Charan ◽

Rajni Kant Shukla ◽

Pranay Agarwal ◽

Swati Misri ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Immunosuppressive Tumor Microenvironment ◽

Tumor Growth And Metastasis ◽

Breast Cancer Growth

Abstract Background: Metastasis is the major cause of mortality in breast cancer; however, the molecular mechanisms remain elusive. In our previous study, we demonstrated that S100A7/RAGE mediates breast cancer growth and metastasis by recruitment of tumor-associated macrophages. However, the downstream S100A7-mediated inflammatory oncogenic signaling cascade that enhances breast tumor growth and metastasis by generating the immunosuppressive tumor microenvironment (iTME) has not been studied. In this present study, we aimed to investigate the S100A7 and cPLA2 cross-talk in enhancing tumor growth and metastasis through enhancing the iTME.Methods: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2 titer. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3(1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effect of S100A7/cPLA2 inhibition on the recruitment of various immune cells.Results: S100A7 and cPLA2 are highly expressed and positively correlated in malignant breast cancer patients. S100A7/RAGE upregulates cPLA2/PGE2 axis in aggressive breast cancer cells. Furthermore, S100A7 is positively correlated with PGE2 in breast cancer patients. Moreover, cPLA2 pharmacological inhibition suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models. Mechanistically, S100A7-mediated activation of cPLA2 enhances the recruitment of immunosuppressive myeloid cells by increasing PGE2 to fuel breast cancer growth and its secondary spread. We revealed that cPLA2 inhibitor mitigates S100A7-mediated breast tumorigenicity by suppressing the iTME. Furthermore, CODEX imaging data showed that cPLA2 inhibition increased the infiltration of CD4+/CD8+ T cells in the TME. Analysis of metastatic breast cancer samples revealed a positive correlation between S100A7/cPLA2 with CD163+ tumor-associated M2-macrophages.Conclusions: Our study shows that cross-talk between S100A7 and cPLA2 plays an important role in enhancing breast tumor growth and metastasis by generating an immunosuppressive tumor microenvironment and reducing infiltration of T cells. Furthermore, S100A7 could be used as a novel non-invasive prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing metastatic breast cancer.

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404. Effect of IL-15 Gene Therapy and mTOR Inhibitor Everolimus on Experimental Metastatic Breast Cancer Growth

Molecular Therapy ◽

10.1016/s1525-0016(16)34739-6 ◽

2013 ◽

Vol 21 ◽

pp. S155-S156

Keyword(s):

Breast Cancer ◽

Gene Therapy ◽

Metastatic Breast Cancer ◽

Mtor Inhibitor ◽

Metastatic Breast ◽

Cancer Growth ◽

Breast Cancer Growth

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Adenoviral Mediated Interleudkin-12 Gene Therapy for Metastatic Breast Cancer

10.21236/ada433855 ◽

2004 ◽

Author(s):

Savio L. Woo

Keyword(s):

Breast Cancer ◽

Gene Therapy ◽

Metastatic Breast Cancer ◽

Metastatic Breast

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Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms22147430 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7430

Author(s):

Hiromi Sato ◽

Ayaka Shimizu ◽

Toya Okawa ◽

Miaki Uzu ◽

Momoko Goto ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Metastatic Breast ◽

Principal Component ◽

Pentose Phosphate ◽

Metastatic Brain Tumors ◽

Pentose Phosphate Pathways ◽

Culture Supernatants

The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine–proline metabolism. Similarly, the metabolome of cancer cells was also altered by astrocyte culture supernatants, and the changes were further amplified in astrocytes exposed to Glu. Inhibition of Glu uptake in astrocytes reduces the variability in cancer cells. Principal component analysis of the cancer cells revealed that all these changes were in the first principal component (PC1) axis, where the responsible metabolites were involved in the metabolism of the arginine–proline, pyrimidine, and pentose phosphate pathways. The contribution of these changes to the tumor microenvironment needs to be further pursued.

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HER2 Gene Amplification by Fluorescence In Situ Hybridization(FISH) as a Predictor of Response to Trastuzumab in Metastatic Breast Cancer

Clinical Breast Cancer ◽

10.1016/s1526-8209(11)70109-4 ◽

2000 ◽

Vol 1 (2) ◽

pp. 105-106

Keyword(s):

Breast Cancer ◽

In Situ Hybridization ◽

Metastatic Breast Cancer ◽

Fluorescence In Situ Hybridization ◽

Gene Amplification ◽

Metastatic Breast ◽

Her2 Gene ◽

Her2 Gene Amplification

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Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2016.12.010 ◽

2017 ◽

Vol 6 ◽

pp. 249-258 ◽

Cited By ~ 9

Author(s):

Cian M. McCrudden ◽

John W. McBride ◽

Joanne McCaffrey ◽

Ahlam A. Ali ◽

Nicholas J. Dunne ◽

...

Keyword(s):

Breast Cancer ◽

Gene Therapy ◽

Metastatic Breast Cancer ◽

Metastatic Breast

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Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling

Mediators of Inflammation ◽

10.1155/2021/7785890 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Fengjie Liu ◽

Lihong Li ◽

Meng Lan ◽

Tengteng Zou ◽

Zhaodi Kong ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Interleukin 1 ◽

Therapeutic Targets ◽

Metastatic Breast ◽

Receptor System ◽

Inflammatory Infiltration ◽

Inflammatory Microenvironment ◽

Incidence And Mortality

Breast cancer is one of the top-ranked cancers for incidence and mortality worldwide. The biggest challenges in breast cancer treatment are metastasis and drug resistance, for which work on molecular evaluation, mechanism studies, and screening of therapeutic targets is ongoing. Factors that lead to inflammatory infiltration and immune system suppression in the tumor microenvironment are potential therapeutic targets. Interleukin-1 is known as a proinflammatory and immunostimulatory cytokine, which plays important roles in inflammatory diseases. Recent studies have shown that interleukin-1 cytokines drive the formation and maintenance of an inflammatory/immunosuppressive microenvironment through complex intercellular signal crosstalk and tight intracellular signal transduction, which were found to be potentially involved in the mechanism of metastasis and drug resistance of breast cancer. Some preclinical and clinical treatments or interventions to block the interleukin-1/interleukin-1 receptor system and its up- and downstream signaling cascades have also been proven effective. This study provides an overview of IL-1-mediated signal communication in breast cancer and discusses the potential of IL-1 as a therapeutic target especially for metastatic breast cancer and combination therapy and current problems, aiming at enlightening new ideas in the study of inflammatory cytokines and immune networks in the tumor microenvironment.

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Resetting the tumor microenvironment to favor anti-tumor immunity after local ablation.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2561 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2561-2561

Author(s):

Corrine A. Nief ◽

Júlia Sroda Agudogo ◽

Alana Gonzales ◽

Rebecca A. Previs ◽

Smita K Nair ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

T Cell ◽

Tumor Microenvironment ◽

Low Dose ◽

Tumor Response ◽

Surgical Excision ◽

Tumor Ablation ◽

Local Ablation

2561 Background: Percutaneous tumor ablation is a non-surgical method of tumor destruction that leaves necrotic tumor debris in situ. Tumor associated antigens released after ablation have the potential to initiate a systemic anti-tumor immune response, however the hostile tumor microenvironment hinders antigen presentation and T cell activity. We hypothesized that resetting the tumor microenvironment with oral sodium bicarbonate to decrease tumor acidity and low-dose cyclophosphamide to deplete pro-tumor immune cells would improve the ability of ablation to initiate anti-tumor immunity. Methods: Tumor growth, overall survival, and metastatic burden was assessed in orthotopic tumor models of triple-negative breast cancer (67NR, 4T1, and E0771). Tumor ablation was performed on palpable tumors using percutaneous ethanol injection (PEI) with 6% ethylcellulose to improve retention in the tumor. Surgical excision was used as a negative control to test the role of in situ tumor debris. Before ablation mice were placed on 200 mM of sodium bicarbonate (SB) in their drinking water and received a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CP). Mice surviving to 60 days after tumor implant without a primary tumor or signs of metastases were considered "cured" and re-challenged with 50e5 tumor cells in the contralateral mammary pad. T cell dependance was assessed with in vivo CD8 depletions. Results: The combination of PEI+SB+CP produced a potent anti-tumor response, curing a majority of mice (5/7 of E0771, 8/12 of 67NR, 7/12 of 4T1). No mice were cured using PEI alone, SB alone, CP alone, or any combination of two therapies (0/51 of E0771, 0/73 of 67NR, 0/75 of 4T1,). Re-challenge tumor growth was hindered in mice cured with PEI+SB+CP. Mice receiving PEI+SB+CP had significantly less metastases and lived longer than mice receiving surgical excision alone or surgical excision with SB+CP. Additionally the anti-metastatic response of PEI+SB+CP was undone when CD8+ T cells were depleted. Conclusions: Here the anti-tumor response of local ablation produced by PEI was enhanced by priming the tumor with low-dose CP and oral SB in metastatic breast cancer. These results suggest that tumor ablation with CP and SB can create a T cell dependent, personalized immune response to a tumor using only low-cost, easily accessible supplies, and the host’s own tumor.

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