Tumor Angiogenesis Research Articles

Role of IL-33/ST2 Pathway in Inflammatory Bowel Disease: An Overview and Future Perspectives

Inflammatory bowel disease (IBD) represents a heterogenous and complex group of idiopathic chronic inflammatory conditions affecting the gastrointestinal tract and other extraintestinal systems with rising global incidences. The interplay of genetic predisposition and environmental factors contributes to its pathogenesis. Among the key cytokines implicated in IBD molecular alterations, IL-33 stands out for its multifaceted roles in both pathogenesis and repair mechanisms. IL-33, known for its action in initiating immune responses, is closely associated with Th2 immunity and is considered a potent inflammatory factor with dual functions, acting both as a pro-inflammatory cytokine and a transcriptional regulator. Primarily expressed by non-hematopoietic cells in the gastrointestinal tract, IL-33 interacts with its receptor, ST2, to modulate immune responses. In IBD, dysregulated IL-33 expression exacerbates mucosal inflammation, compromising barrier integrity and promoting tissue damage and fibrosis. Additionally, IL-33 plays a complex role in IBD-related colorectal cancer (CRC), affecting tumor progression and angiogenesis. This review summarizes the multifaceted roles of IL-33 in gastrointestinal health and disease, emphasizing its significance in the pathogenesis of IBD and CRC. Moreover, we thought it of interest to provide new insights into potential therapeutic avenues targeting IL-33 signaling for the management of these debilitating conditions.

Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression

Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)—the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.

Fibrinogen and tumors

Elevated plasma fibrinogen (Fg) levels consistently correlate with an unfavorable prognosis in various tumor patient cohorts. Within the tumor microenvironment, aberrant deposition and expression of Fg have been consistently observed, interacting with multiple cellular receptors and thereby accentuating its role as a regulator of inflammatory processes. Specifically, Fg serves to stimulate and recruit immune cells and pro-inflammatory cytokines, thereby contributing to the promotion of tumor progression. Additionally, Fg and its fragments exhibit dichotomous effects on tumor angiogenesis. Notably, Fg also facilitates tumor migration through both platelet-dependent and platelet-independent mechanisms. Recent studies have illuminated several tumor-related signaling pathways influenced by Fg. This review provides a comprehensive summary of the intricate involvement of Fg in tumor biology, elucidating its multifaceted role and the underlying mechanisms.

Traditional Chinese Medicine for Cancer Treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

Angiogenesis Still Plays a Crucial Role in Human Melanoma Progression

Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME.

Flavokawain C inhibits glucose metabolism and tumor angiogenesis in nasopharyngeal carcinoma by targeting the HSP90B1/STAT3/HK2 signaling axis

ObjectiveOver the past decade, heat shock protein 90 (HSP90) inhibitors have emerged as promising anticancer drugs in solid and hematological malignancies. Flavokawain C (FKC) is a naturally occurring chalcone that has been found to exert considerable anti-tumor efficacy by targeting multiple molecular pathways. However, the efficacy of FKC has not been studied in nasopharyngeal carcinoma (NPC). Metabolic abnormalities and uncontrolled angiogenesis are two important features of malignant tumors, and the occurrence of these two events may involve the regulation of HSP90B1. Therefore, this study aimed to explore the effects of FKC on NPC proliferation, glycolysis, and angiogenesis by regulating HSP90B1 and the underlying molecular regulatory mechanisms.MethodsHSP90B1 expression was analyzed in NPC tissues and its relationship with patient’s prognosis was further identified. Afterward, the effects of HSP90B1 on proliferation, apoptosis, glycolysis, and angiogenesis in NPC were studied by loss-of-function assays. Next, the interaction of FKC, HSP90B1, and epidermal growth factor receptor (EGFR) was evaluated. Then, in vitro experiments were designed to analyze the effect of FKC treatment on NPC cells. Finally, in vivo experiments were allowed to investigate whether FKC treatment regulates proliferation, glycolysis, and angiogenesis of NPC cells by HSP90B1/EGFR pathway.ResultsHSP90B1 was highly expressed in NPC tissues and was identified as a poor prognostic factor in NPC. At the same time, knockdown of HSP90B1 can inhibit the proliferation of NPC cells, trigger apoptosis, and reduce glycolysis and angiogenesis. Mechanistically, FKC affects downstream EGFR phosphorylation by regulating HSP90B1, thereby regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. FKC treatment inhibited the proliferation, glycolysis, and angiogenesis of NPC cells, which was reversed by introducing overexpression of HSP90B1. In addition, FKC can affect NPC tumor growth and metastasis in vivo by regulating the HSP90B1/EGFR pathway.ConclusionCollectively, FKC inhibits glucose metabolism and tumor angiogenesis in NPC by targeting the HSP90B1/EGFR/PI3K/Akt/mTOR signaling axis.

Characterization of Tumor Angiogenesis in Gastric Carcinomas at Different Stages of Their Progression

Characterization of Tumor Angiogenesis in Gastric Carcinomas at Different Stages of Their Progression

The deubiquitinase USP7 and E3 ligase TRIM21 regulate vasculogenic mimicry and malignant progression of RMS by balancing SNAI2 homeostasis

BackgroundRhabdomyosarcoma (RMS) is a rare malignancy and the most common soft tissue sarcoma in children. Vasculogenic mimicry (VM) is a novel tumor microcirculation model different from traditional tumor angiogenesis, which does not rely on endothelial cells to provide sufficient blood supply for tumor growth. In recent years, VM has been confirmed to be closely associated with tumor progression. However, the ability of RMS to form VM has not yet been reported.MethodsImmunohistochemistry, RT-qPCR and western blot were used to test the expression level of SNAI2 and its clinical significance. The biological function in regulating vasculogenic mimicry and malignant progression of SNAI2 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of SNAI2.ResultsOur study indicated that SNAI2 was abnormally expressed in patients with RMS and RMS cell lines and promoted the proliferation and metastasis of RMS. Through cell tubule formation experiments, nude mice Matrigel plug experiments, and immunohistochemistry (IHC), we confirmed that RMS can form VM and that SNAI2 promotes the formation of VM. Due to SNAI2 is a transcription factor that is not easily drugged, we used Co-IP combined with mass spectrometry to screen for the SNAI2-binding protein USP7 and TRIM21. USP7 depletion inhibited RMS VM formation, proliferation and metastasis by promoting SNAI2 degradation. We further demonstrated that TRIM21 is expressed at low levels in human RMS tissues and inhibits VM in RMS cells. TRIM21 promotes SNAI2 protein degradation through ubiquitination in the RMS. The deubiquitinase USP7 and E3 ligase TRIM21 function in an antagonistic rather than competitive mode and play a key role in controlling the stability of SNAI2 to determine the VM formation and progression of RMS.ConclusionOur findings reveal a previously unknown mechanism by which USP7 and TRIM21 balance the level of SNAI2 ubiquitination, determining RMS vasculogenic mimicry, proliferation, and migration. This new mechanism may provide new targeted therapies to inhibit the development of RMS by restoring TRIM21 expression or inhibiting USP7 expression in RMS patients with high SNAI2 protein levels.

Abstract PO2-01-01: Biophysical simulation using DCE-MRI to forecast response to NAT in HER2+ patients, with glucose characterization and orthogonal validation using FDG-PET

Abstract Background: Metabolic reprogramming and tumor angiogenesis are two tightly linked hallmarks of cancer. Regions of high metabolic activity within a tumor can become hypoxic or nutrient starved, eliciting a cascade of pro-angiogenic signals that can lead to increased tumor perfusion and in turn greater metabolic activity. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) are two imaging methods commonly used in the diagnosis of cancer; the former can be also used to identify the perfusion of the tumor microenvironment (TME) and the latter provides a coarse readout of glucose metabolic activity. Here, we are presented with a unique cohort of patients who underwent DCE-MRI, 18FDG-PET and 64Cu-DOTA-Traztuzumab offering potential to perform a pilot analysis. First, we characterize the performance of our perfusion model SimBioSys- Microvasculature (SBS-MV) through a stability analysis, as well as comparison with two PET modalities. Finally, we use this model in 3D simulations of individual HER2+ breast cancer patients to forecast responses to neoadjuvant chemotherapy (NAT). Methods: SBS-MV is a modified Tofts model for pharmacokinetic modeling of DCE-MRI data, utilizing a tissue segmentation model developed in-house to inform parameter fits and ensure that the derived parameters fall within acceptable values on a tissue-by-tissue level, in addition its function for standard fitting of DCE time-course data. We first evaluated the stability of the SBS-MV model by analyzing a separate cohort of 10 patients who underwent ultrafast DCE-MRI. Temporal undersampling was performed on the original high temporal resolution data to mimic low temporal resolution from standard-of-care (SoC) DCE studies. Both datasets were processed with SBS-MV model. Next, we analyzed data from a cohort of 18 patients, each of whom underwent a pre-NAT SoC DCE-MRI study, a mid-treatment FDG PET/CT study, and a mid-treatment 64Cu-DOTA-Trastuzumab/CT study during treatment. Tissue segmentation and SBS-MV fits were performed on the pre-NAT DCE MRI. Tightly cropped boxes encompassing the tumor in the 3D SBS-MV volumes as well as the PET volumes were created. Using these identified regions, all summary statistics were calculated and cross-correlated between imaging modalities. Results: SBS-MV was stable to SoC-mimicking temporally undersampled ultrafast DCE MRI series, demonstrating relatively little variability in the output parameters (a voxel wise median deviation of approximately 0.005 min-1 ). Further, we demonstrate that SBS-MV parameters (Ktrans, ve) are correlated with FDG SUVSA and 64Cu SUVSA. In addition, the glucose concentrations used in the biophysical simulations were correlated with FDG SUVSA, indicating that downstream applications of the SBS-MV models still carry this information about perfusion. Finally, using SBS-MV, our biophysical simulations of HER2-targeted therapy accurately predict patient response. In this small cohort, our biophysical simulation platform performed well, yielding predictive accuracy of 0.83, with sensitivity and specificity of 0.83 and 0.83, respectively. These performance metrics are in line with previously published reports. Conclusion: Our MV model is capable of extracting biologically meaningful perfusion parameters from standard clinical DCE MRI time series, providing the same benefits of a comprehensive kinetic analysis, without impacting current clinical workflow. This approach could be used in both the research and clinical settings, offering actionable information on what drives individual patient therapeutic response for a more personalized care. Citation Format: John Whitman, Vikram Adhikarla, Russell Rockne, Lusine Tumyan, Joanne Mortimer, Wei Huang, Joseph Peterson, Dorys Lopez-Ramos, John Cole. Biophysical simulation using DCE-MRI to forecast response to NAT in HER2+ patients, with glucose characterization and orthogonal validation using FDG-PET [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-01.

Abstract PO1-18-11: Imaging of tumour microvasculature using high-resolution contrast enhanced ultrasound together with markers of proliferation/angiogenesis/vascular mimicry to characterise response to NACT in TNBC

Abstract Background: In the UK, triple-negative breast cancer (TNBC) comprises 10-15% of breast cancer diagnoses annually. TNBC represents a clinical challenge due to a lack of expression of three treatable drug targets, namely oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER-2). The mainstay of treatment involves the use of neoadjuvant chemotherapy (NACT) followed by surgical excision where up to 50% of patients will achieve a pathological complete response (pCR). The addition of neo-adjuvant immunotherapy may increase the pCR rate to 60%. The presence of lymphatics and blood vessels within/around malignant tumours plays a role in cancer progression as does the formation of new blood vessels (angiogenesis). The vascular endothelial growth factor (VEGF) family and their receptors (VEGFRs) play an important role in angiogenesis as well as promoting the growth and survival of cancer cells. VEGFR is frequently overexpressed in TNBC and promotes changes in vascular endothelial cells, the basement membrane and the surrounding extracellular matrix. Co-expression of epidermal growth factor receptor (EGFR) and VEGFR enhances tumour growth and angiogenesis in an autocrine and paracrine manner. An alternate mechanism for tumour microcirculation in tumours is vasculogenic mimicry (VM). This is distinct from classical tumour angiogenesis. The presence of VM is associated with poor overall survival in breast cancer patients and anti-angiogenic treatment of TNBC may even promote tumour growth, proliferation and metastasis by stimulating VM. Conventional imaging techniques such as B-mode ultrasound and MRI are commonly used to monitor disease response in the breast but have limited accuracy in predicting pCR or residual disease. High-resolution contrast-enhanced ultrasound (HRCEUS) may offer a more accurate test to monitor TNBC response to NACT. This method utilises intravenously injected microbubbles, which consist of a gas core with an outer shell of lipid/albumin to image tumour microvasculature as well as gross tumour morphology. Trial Design: Single-centre study to evaluate HRCEUS to image the microvasculature of TNBC tumours in patients undergoing (NACT) and correlate imaging results with established markers of angiogenesis, proliferation and vasculogenic mimicry. Eligibility Criteria: Female, 18 to 60 years, histologically confirmed invasive TNBC with planned NACT, able to consent and in the Investigator’s opinion, adhering to the trial recommendations and governance. Aims: To investigate if imaging changes in the tumour microvasculature indicate a response to NACT and are reflected in the expression of proliferative markers. To determine whether changes in the tumour microvasculature and disease response are driven by angiogenesis +/- VM. To investigate whether overall disease response and changes in the microvasculature are influenced by the basal type phenotype or germline mutations in BRCA 1/2. Investigate patient satisfaction with the contrast ultrasound test. Statistical Methods: Quantify HRCEUS imaging characteristics of microvasculature at 3 treatment points. Compare this with the results of conventional imaging and the histopathological results of surgical excision at the end of NACT. Quantify immunohistochemical markers of angiogenesis, proliferation and VM at three treatment points and compare this with HRCEUS. Determine phenotype of all cases using immunohistochemistry to identify the basal Perform subtype analysis to assess if the basal phenotype is associated with imaging and immunohistochemical changes in the microvasculature during NACT. Test patients for germline BRCA1/2 gene mutations. Perform subtype analysis to assess if germline BRCA1/2 mutations are associated with imaging and immunohistochemical changes in the microvasculature during NACT. Present accrual (2 patients) and target accrual (5 patients) Contact details: j.rait@nhs.net Citation Format: Jaideep Rait, Michelle Garrett, Catherine Harper-Wynne, Sonia Saw, Mengxing Tang, Priya Palanisamy, Matthieu TOULEMONDE, Karina Cox. Imaging of tumour microvasculature using high-resolution contrast enhanced ultrasound together with markers of proliferation/angiogenesis/vascular mimicry to characterise response to NACT in TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-11.

Abstract PO2-27-04: Unravelling the role of FGFR1 in innate immune sensing and endocrine resistance in breast cancer

Abstract Fibroblast Growth Factor Receptor 1 (FGFR1) has emerged as a critical player in various cancer types, including breast cancer. FGFR1 alterations, including gene amplification, overexpression, and activating mutations, have been identified in subsets of breast cancers, contributing to aberrant signaling pathways that promote tumor growth, angiogenesis, and metastasis. Our current research endeavors are directed towards unravelling the intricate mechanistic underpinnings of FGFR1's dual impact on breast tumor progression, specifically its contribution to endocrine resistance and its regulatory role in innate immune sensing and subsequent induction of Type 1 interferons (IFNs) Our investigative efforts have previously established a direct association between FGFR1 and endocrine resistance in hormone receptor positive T47D breast cancer cells. Moreover, a remarkable and distinct inverse correlation linking FGFR1 expression to the Type 1 IFN response was observed. We noticed that in vitro stimulation of T47D cells with Type 1 interferons induces the expression of FGFR1 and ESR1, thereby suppressing the interferon-stimulated genes. Interestingly, we observed that the FGFR1-mediated suppression of the Type 1 interferon response is associated with intracellular nucleic acid sensors, specifically toll-like receptors TLR7 and TLR9. Furthermore, we found that the inhibition of FGFR kinase enhances the expression of IFN-alpha, IFN-beta, TLR7, and TLR9 in T47D cells when stimulated with the TLR7 agonist loxoribine. These results strongly suggest that FGFR1 functions as an innate checkpoint and may be exploited by tumor cells to dampen Type 1 interferon responses, thereby inhibiting antitumor immunity in hormone receptor-positive breast cancer. Citation Format: Sushil Dhakal, Torbjørn Amundsen Lien, Jens Henrik Norum, Helga Bergholtz, Helene Midtun Flatekvål, Therese Sørlie. Unravelling the role of FGFR1 in innate immune sensing and endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-04.

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial

Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). From Jan 2021 to Aug 2022, 48patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N=45), Grade 3 or 4 treatment emergent adverse events occurred in 29patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Natural products’ antiangiogenic roles in gynecological cancer

Gynecological cancers pose a significant threat to women’s health. Although the pathogenesis of gynecological cancer remains incompletely understood, angiogenesis is widely acknowledged as a fundamental pathological mechanism driving tumor cell growth, invasion, and metastasis. Targeting angiogenesis through natural products has emerged as a crucial strategy for treating gynecological cancer. In this review, we conducted comprehensive searches in PubMed, Embase, Web of Science, Science Direct, and CNKI databases from the first publication until May 2023 to identify natural products that target angiogenesis in gynecologic tumors. Our findings revealed 63 natural products with anti-angiogenic activity against gynecological cancer. These results underscore the significance of these natural products in augmenting their anticancer effects by modulating other factors within the tumor microenvironment via their impact on angiogenesis. This article focuses on exploring the potential of natural products in targeting blood vessels within gynecological cancer to provide novel research perspectives for targeted vascular therapy while laying a solid theoretical foundation for new drug development.

Enhancing anticancer activity of macrophages through rational drug combinations.

Targeting tumor-associated macrophages (TAMs) is an emerging approach being tested in multiple clinical trials. TAMs, depending on their differentiation state, can exhibit pro- or antitumorigenic functions. For example, the M2-like phenotype represents a protumoral state that can stimulate tumor growth, angiogenesis, metastasis, therapy resistance, and immune evasion by expressing immune checkpoint proteins. In this issue of the JCI, Vaccaro and colleagues utilized an innovative drug screen approach to demonstrate that targeting driver oncogenic signaling pathways concurrently with anti-CD47 sensitizes tumor cells, causing them to undergo macrophage-induced phagocytosis. The combination treatment altered expression of molecules on the tumor cells that typically limit phagocytosis. It also reprogrammed macrophages to an M1-like antitumor state. Moreover, the approach was generalizable to tumor cells with different oncogenic pathways, opening the door to precision oncology-based rationale combination therapies that have the potential to improve outcomes for patients with oncogene-driven lung cancers and likely other cancer types.

Trichinella spiralis Larval Extract as a Biological Anti-Tumor Therapy in a Murine Model of Ehrlich SolidCarcinoma.

Trichinella spiralis (T. spiralis) is an immunomodulating parasite that can adversely affect tumor growth and extend host lifespan. The aim of this study was to elucidate the mechanisms by which T. spiralis larval antigens achieve this effect using Ehrlich solid carcinoma (ESC) murine model. Assessment was done by histopathological and immunohistochemical analysis of caspase-3, TNF-α, Ki-67 and CD31. Additionally, Bcl2 and Bcl2-associated protein X (Bax) relative gene expression was assessed by molecular analysis for studying the effect of T. spiralis crude larval extract (CLE) antigen on tumor necrosis, apoptosis, cell proliferation and angiogenesis. We found that both T. spiralis infection and CLE caused a decrease in the areas of necrosis in ESC. Moreover, they led to increased apoptosis through activation of caspase-3, up-regulation of pro-apoptotic gene, Bax and down-regulation of anti-apoptotic gene, Bcl2. Also, T. spiralis infection and CLE diminished ESC proliferation, as evidenced by decreasing Ki-67. T. spiralis infection and CLE were able to suppress the development of ESC by inhibiting tumor proliferation, inducing apoptosis and decreasing tumor necrosis, with subsequent decrease in tumor metastasis. T. spiralis CLE antigen may be considered as a promising complementary immunotherapeutic agent in the treatment of cancer.

β-hydroxybutyrate Restrains Colitis-Associated Tumorigenesis by Inhibiting HIF-1α-Mediated Angiogenesis

Decreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the (Azoxymethane) AOM /(Dextran Sulfate Sodium) DSS-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.

MnO2 nanoparticle improves the immunosuppressive characteristics of tumor-associated mesenchymal stromal cells

Tumor-associated marrow mesenchymal stem/stromal cells have immunosuppressive effects on immune cells within the tumor microenvironment in various cancers. However, effective treatments targeting these cells are currently limited. Here, we developed a nanoparticle of MnO2 aiming to inhibit the immunosuppressive properties of Tumor-Associated Marrow Mesenchymal stem/stromal cells. We investigated the physicochemical characteristics of MnO2 and its potential for alleviating hypoxia in IL17 and IFNγ transformed Tumor-Associated Marrow Mesenchymal stem/stromal cells. The Tumor-Associated Marrow Mesenchymal stem/stromal cells had higher expression level of chemokines and immunosuppressors, which promotes the progression of tumors and inhibits the immune cells, leading to tumor metastasis and angiogenesis. After treatment of the nanoparticle of MnO2, the expression level of chemokines had significantly decreased due to the unique properties of MnO2. Furthermore, the nanoparticle decreased the expression level of immunosuppressors of Tumor-Associated Marrow Mesenchymal stem/stromal cells and rescued the proliferation of T lymphocytes cocultured with the cells. In conclusion, our findings demonstrate that MnO2 nanoparticles effectively improve the hypoxic microenvironment and alleviate immunosuppression caused by Tumor-Associated Marrow Mesenchymal stem/stromal cells. The utilization of this novel approach exhibits promising potential as a therapeutic strategy for addressing diverse types of cancers.

Incorporation of immunotherapies and nanomedicine to better normalize angiogenesis-based cancer treatment.

Neoadjuvant targeting of tumor angiogenesis has been developed and approved for the treatment of malignant tumors. However, vascular disruption leads to tumor hypoxia, which exacerbates the treatment process and causes drug resistance. In addition, successful delivery of therapeutic agents and efficacy of radiotherapy require normal vascular networks and sufficient oxygen, which complete tumor vasculopathy hinders their efficacy. In view of this controversy, an optimal dose of FDA-approved anti-angiogenic agents and combination with other therapies, such as immunotherapy and the use of nanocarrier-mediated targeted therapy, could improve therapeutic regimens, reduce the need for administration of high doses of chemotherapeutic agents and subsequently reduce side effects. Here, we review the mechanism of anti-angiogenic agents, highlight the challenges of existing therapies, and present how the combination of immunotherapies and nanomedicine could improve angiogenesis-based tumor treatment.

PH-responsive drug-loaded peptides enhance drug accumulation and promote apoptosis in tumor cells

Breast cancer is the most widespread form of cancer and the main contributor to cancer-related fatalities among women. The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising.

Screening and construction of nanobodies against human CD93 using phage libraries and study of their antiangiogenic effects

BackgroundCluster of Differentiation 93 (CD93) plays an important role in angiogenesis and is considered an important target for inhibiting tumor angiogenesis, but there are currently no therapeutic antibodies against CD93 in the clinic. Thus, we describe the screening of novel nanobodies (Nbs) targeting human CD93 from a phage library of shark-derived Nbs.MethodsScreening and enrichment of phage libraries by enzyme-linked immunosorbent assay (ELISA). Anti-CD93 Nbs were purified by expression in E. coli. The binding affinity of anti-CD93 Nbs NC81/NC89 for CD93 was examined by flow cytometry (FC) and ELISA. The thermal stability of NC81/NC89 was examined by ELISA and CD spectroscopy. Afterward, the anti-angiogenic ability of NC81/NC89 was examined by MTT, wound healing assay, and tube formation assay. The expression level of VE-cadherin (VE-Ca) and CD93 was detected by Western Blot (WB). The binding sites and binding forms of NC81/NC89 to CD93 were analyzed by molecular docking.ResultsThe anti-CD93 Nbs were screened in a phage library, expressed in E. coli, and purified to >95% purity. The results of FC and ELISA showed that NC81/NC89 have binding ability to human umbilical vein endothelial cells (HUVECs). The results of ELISA and CD spectroscopy showed that NC81/NC89 retained the ability to bind CD93 at 80°C and that the secondary structure remained stable. In vitro, the results showed that NC81 and NC89 significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) as well as tube formation on Matrigel. Western Blot showed that NC81 and NC89 also inhibited the expression of VE-Ca thereby increasing vascular permeability. It was found during molecular docking that the CDR regions of NC81 and NC89 could be attached to CD93 by strong hydrogen bonds and salt bridges, and the binding sites were different.ConclusionWe have successfully isolated NC81 and NC89, which bind CD93, and both Nbs significantly inhibit angiogenesis and increase vascular permeability. These results suggest that NC81 and NC89 have potential clinical applications in angiogenesis-related therapies.