A bibliometric analysis of the research landscape on vascular normalization in cancer.

Tumor vascular normalization profoundly affects the advancement of cancer therapy. Currently, with the rapid increase in research on tumor vascular normalization, few analytical and descriptive studies have investigated the trends in its development, key research power, present research hotspots, and future outlooks. In this study, articles and reviews published between January 1, 2003, and October 29, 2022 were retrieved from Web of Science database. Subsequently, published research trends, countries/regions, institutions, authors, journals, references, and keywords were analyzed based on traditional bibliometric laws (such as Price's exponential growth, Bradford's, Lotka's, and Zipf's). Our results showed that the last two decades have seen an increase in tumor vascular normalization research. USA emerged as the preeminent contributor to the field, boasting the highest H-index and accruing the greatest quantity of publications and citations. Among institutions, Massachusetts General Hospital and Harvard University made significant contributions, and Professor RK Jain was identified as a key leader in this field. Out of 583 academic journals, Cancer Research and Clinical Cancer Research published the most articles on vascular normalization. The research focal points in the field primarily include immunotherapy, tumor microenvironments, nanomedicine, and emerging frontier themes such as metabolism and mechanomedicine. Concurrently, the challenges of vascular normalization in cancer are discussed as well. In conclusion, the study presented a thorough analysis of the literature covering the past 20 years on vascular normalization in cancer, highlighting leading countries, institutions, authors, journals, and the emerging research focal points in this field. Future studies will advance the ongoing efforts in the field of tumor vascular normalization, aiming to enhance our ability to effectively manage and treat cancer.

A therapeutic HPV16 E7 vaccine in combination with active anti-FGF-2 immunization synergistically elicits robust antitumor immunity in mice.

FGF-2 accumulates in many tumor tissues and is closely related to the development of tumor angiogenesis and the immunosuppressive microenvironment. This study aimed to investigate whether active immunization against FGF-2 could modify antitumor immunity and enhance the efficacy of an HPV16 E7-specific therapeutic vaccine. Combined immunization targeting both FGF-2 and E7 significantly suppressed tumor growth, which was accompanied by significantly increased levels of IFN-γ-expressing splenocytes and effector CD8 T cells and decreased levels of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells(MDSCs) in both the spleen and tumor; in addition, the levels of FGF-2 and neovascularization in tumors were decreased in the mice receiving the combined immunization, and tumor cell apoptosis was promoted. The combination of an HPV16 E7-specific vaccine and active immunization against FGF-2 significantly enhances antitumor immune responses in mice with TC-1 tumors, indicating a promising strategy for tumor immunotherapy.

Modified bacterial outer membrane vesicles induce autoantibodies for tumor therapy.

Using monoclonal antibodies to block tumor angiogenesis has yielded effective antitumor effects. However, this treatment method has long cycles and is very expensive; therefore, its long-term and extensive application is limited. In this study, we developed a nanovaccine using bacterial biomembranes as carriers for antitumor therapy. The whole basic fibroblast growth factor (BFGF) molecule (154 amino acids (aa)) was loaded onto bacterial outer membrane vesicles (OMVs) using gene recombination technology. The strong adjuvant effect of OMVs was used to induce the host to produce anti-BFGF autoantibodies. We proved that persistent anti-BFGF autoantibodies can be induced in mice after only 3 immunizations to antagonize BFGF functions. The effects included multiple tumor suppression functions, including inhibition of tumor angiogenesis, induction of tumor cell apoptosis, reversal of tumor immune barriers, and promotion of tumor-specific cytotoxic T lymphocytes (CTLs), eventually causing tumor regression. We confirmed that bacterial biomembranes can be used as a vaccine delivery system to induce the production of antibodies against autoantigens, which may be used for tumor therapy. This study expands the application fields of bacterial biomembrane systems and provides insight for tumor immunotherapy other than monoclonal antibody technology. STATEMENT OF SIGNIFICANCE: In this study, we proved that bacteria-released outer membrane vesicles (OMVs) modified via genetic engineering can be used as a vaccine carrier to break autoimmune tolerance and induce the body to produce autoantibodies to antagonize pathological molecules and block pathological signaling pathways for tumor therapy. OMVs naturally released by bacteria were used to successfully load the full-length BFGF protein (154 aa). We proved that persistent anti-BFGF autoantibodies can be induced in tumor-bearing mice after only 3 immunizations to effectively inhibit tumors. Furthermore, the production of these antibodies successfully inhibited tumor angiogenesis, promoted tumor cell apoptosis, reversed the tumor immunosuppressive microenvironment, increased the cytotoxic T lymphocyte (CTL) reaction, and eventually inhibited tumor growth.

Virus-Like Particles Presenting the FGF-2 Protein or Identified Antigenic Peptides Promoted Antitumor Immune Responses in Mice.

BACKGROUND: Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms. PURPOSE: This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses. METHODS: A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to virus-like particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model. RESULTS: Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8+ IFN-γ+ cytotoxic T lymphocytes (CTLs) and CD4+ IFN-γ+ Th1 cells were significantly increased, whereas the immunosuppressive cells CD4+ CD25+ FOXP3+ Treg cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses. CONCLUSION: Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.

Local mucosal immunization of self-assembled nanofibers elicits robust antitumor effects in an orthotopic model of mouse genital tumors.

Human papillomavirus (HPV) is the identified causative agent of cervical cancer. Current therapeutic HPV vaccine candidates lack significant clinical efficacy, which can be attributed to insufficient activation of effector cells, lack of effective modification of the immunosuppressive tumor microenvironment, and the limitations of applied tumor models for preclinical vaccine evaluation. Here, a mouse model of orthotopic genital tumors was used to assess the effect of self-assembled nanofibers on eliciting a robust antitumor response via local mucosal immunization. A candidate vaccine was obtained by fusing HPV16 E744-62 to the self-assembling peptide Q11, which was assembled into nanofibers in a salt solution. Mice bearing an established genital TC-1 tumor were immunized with nanofibers through the intravaginal, intranasal, or subcutaneous route. Mucosal vaccination, especially via the intravaginal route, was more effective for suppressing tumor growth than subcutaneous immunization. The potential underlying mechanisms include promoting the systemic generation and tumor accumulation of antigen-specific cytotoxic T lymphocytes expressing high levels of interferon (IFN)-γ or granzyme-B, and reducing the tumor infiltration of immunosuppressive regulatory T cells and myeloid-derived suppressor cells. The levels of IFN-γ, the chemokines CXCL9 and CXCL10, and CXCR3+CD8+ T cells were significantly increased in tumor tissues, which may account for the improved recruitment of effector T cells into the tumor. Local mucosal immunization of nanofibers via the intravaginal route represents a new and promising vaccination strategy for the treatment of genital tumor lesions such as cervical cancer.

Potential role of the antimicrobial peptide Tachyplesin III against multidrug-resistant P. aeruginosa and A. baumannii coinfection in an animal model.

BACKGROUND: Tachyplesin III, an antimicrobial peptide (AMP), provides protection against multidrug-resistant (MDR) bacterial infections and shows cytotoxicity to mammalian cells. Mixed bacterial infections, of which P. aeruginosa plus A. baumannii is the most common and dangerous combination, are critical contributors to the morbidity and mortality of long-term in-hospital respiratory medicine patients. Therefore, the development of effective therapeutic approaches to mixed bacterial infections is urgently needed. METHODS AND RESULTS: In this study, we demonstrated that compared with individual infections, mixed infections with MDR bacteria P. aeruginosa and A. baumannii cause more serious diseases, with increased pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) and chemokines (MCP-1/MIP-2) and reduced mouse survival. In vitro treatment with Tachyplesin III enhanced phagocytosis in a mouse alveolar macrophage cell line (MH-S). Strikingly, in vivo, Tachyplesin III demonstrated a potential role against mixed-MDR bacterial coinfection. The bacterial burden in bronchoalveolar lavage fluid (BALF) was significantly reduced in the Tachyplesin III-treated group. In addition, a systemic reduction in pro-inflammatory cytokines and decreased lung injury occurred with Tachyplesin III therapy. CONCLUSION: Therefore, our study demonstrated that Tachyplesin III represents a potential therapeutic treatment against mixed-MDR bacterial infection in vivo, which sheds light on the development of therapeutic strategies against mixed-MDR bacterial infections.

Pretreatment with cathelicidin-BF ameliorates Pseudomonas aeruginosa pneumonia in mice by enhancing NETosis and the autophagy of recruited neutrophils and macrophages.

Although the antimicrobial peptide cathelicidin-BF shows minimal cytotoxicity in mammalian cells and has excellent direct killing effects on multidrug-resistant clinical pathogens such as Pseudomonas aeruginosa, its clinical application is precluded by its high sensitivity to serum proteases. Here, we demonstrate that intravenous administration of cathelicidin-BF after P. aeruginosa infection did not increase the survival rate of mice with acute pneumonia but that pretreatment with cathelicidin-BF ameliorated pneumonia by effectively activating innate immunity. Enhanced neutrophil extracellular trap (NET) activation and release (NETosis) are key processes for capturing and killing bacteria, concomitantly enhanced macrophage clearance activity, including phagocytosis and autophagy, may eliminate NETs early enough to prevent severe tissue damage. Our study not only suggests a possible approach for applying cathelicidin-BF in vivo but also provides a possible defense strategy against multidrug-resistant pathogens, i.e., efficiently activation of innate immunity.