Tumor Blood Vessels Research Articles

Voluntary wheel running reduces tumor growth and increases capillarity in the heart during doxorubicin chemotherapy in a murine model of breast cancer.

Introduction: The possible beneficial effects of physical activity during doxorubicin treatment of breast cancer need further investigation as many of the existing studies have been done on non-tumor-bearing models. Therefore, in this study, we aim to assess whether short-term voluntary wheel-running exercise during doxorubicin treatment of breast cancer-bearing mice could induce beneficial cardiac effects and enhance chemotherapy efficacy. Methods: Murine breast cancer I3TC cells were inoculated subcutaneously to the flank of female FVB mice (n = 16) that were divided into exercised and non-exercised groups. Two weeks later, doxorubicin treatment was started via intraperitoneal administration (5mg/kg weekly for 3weeks). Organs were harvested a day after the last dose. Results: The tumor volume over time was significantly different between the groups, with the exercising group having lower tumor volumes. The exercised group had increased body weight gain, tumor apoptosis, capillaries per cardiomyocytes, and cardiac lactate dehydrogenase activity compared to the unexercised group, but tumor blood vessel density and maturation and tumor and cardiac HIF1-α and VEGF-A levels did not differ from those of the non-exercised group. Discussion: We conclude that even short-term light exercise such as voluntary wheel running exercise can decrease the subcutaneous mammary tumor growth, possibly via increased tumor apoptosis. The increase in cardiac capillaries per cardiomyocytes may also have positive effects on cancer treatment outcomes.

Homologous-magnetic dual-targeted metal-organic framework to improve the Anti-hepatocellular carcinoma efficacy of PD-1 inhibitor

The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone IIA (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal–organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.

In situ assembly FeS2-tetrathiomolybdate nanosheets for imaging-guided tumor vascular collapse and amplified catalytic therapy

Catalytic therapy has recently gained considerable attention as a novel tumor microenvironment (TME)-responsive treatment. While conventional nano-catalysts have demonstrated the ability to induce the death of tumor cells through oxidative damage via the generation of reactive oxygen species (ROS), their therapeutic efficacy is impeded by several factors, including limited tissue penetration depth and suboptimal catalytic efficiency. Herein, the FeS2-tetrathiomolybdate (FeS2-TTM) nanosheet was synthesized via in-situ self-assembled in the specific redox TME using metal precursors of divalent iron and tetrathiomolybdate, and these metal precursors could easily enter tumor cells through vascular penetration to avoid the blood-brain barrier. This nanosheet has been proved to possess peroxidase (POD)-like catalytic activity, which overcomes the limitations of traditional nanoparticals by the bimetallic electron transfer effect in the TME to amplify the catalytic treatment effect. Importantly, it retains the chelating copper characteristics of TTM, and inhibits tumor angiogenesis by depriving the necessary copper in cells and angiogenesis, resulting in vascular embolization to cause tumor blood vessels to collapse. Additionally, it can also act as a nanoprobe that supports both real-time fluorescence imaging monitoring and T1/T2 dual-modality magnetic resonance imaging (MRI). As a promising nanomaterial, this new type of in-situ self-assembled nanosheet provides more varieties for the construction of an integrative platform of tumor diagnosis and treatment.

A dual drug-loaded tumor vasculature-targeting liposome for tumor vasculature disruption and hypoxia-enhanced chemotherapy

Vascular disrupting agents (VDAs) can destroy tumor vasculature and lead to tumor ischemia and hypoxia, resulting in tumor necrosis. However, VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells. Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome. Here, we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA, which can specifically target tumor vessels and stroma) and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride (AQ4N) and a VDA combretastatin A4 (CA4), respectively. CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels, which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region. As a consequence, AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment. The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro. In addition, in vivo experiments confirm the excellent tumor-targeting/accumulation, tumor vasculature-damaging, and tumor inhibition effects of the liposome. This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection, and is expected to benefit the future development of effective antitumor liposomal drugs.

Intraosseous cavernous hemangioma of parietal bone: A case report and literature review

Introduction and background: Intraosseous Hemangiomas or Primary Intraosseous Hemangiomas (PIH) are slowgrowing innocuous blood vessel tumors that make up less than 1% of all bone malignancies [1-4]. These lesions are estimated to account for 0.2 percent of all benign skull tumors [4-8], with a clear female predisposition (3:1) [2]. Prior trauma to the region is thought to be the most prevalent cause of intraosseous hemangiomas. They bleed profusely when removed or biopsied; therefore, preoperative diagnosis of the lesion’s vascular character is critical [8]. They are most frequently seen in the vertebral skeleton, although they can also be found in the calvarium and facial bones. The temporal bone is the most prevalent place in the head after the vertebral skeleton, followed by the parietal, mandible, malar, and zygomatic areas [8]. In this case report, we discuss the case of a 9-year-old male who presented with a large soft mass in his right parietal region.

Noninvasive Visualization of Tumor Blood Vessels within Hepatocellular Carcinoma by Application of Superb Microvascular Imaging to Contrast-Enhanced Ultrasonography.

The combination or sequential use of systemic therapies, such as lenvatinib and locoregional therapies, can improve the curability rate of hepatocellular carcinoma. This is based on the notion that lenvatinib remodels abnormal tumor vessels into normal vessels, potentially enhancing the efficacy of locoregional therapies. In this case report, we achieved noninvasive visualization of tumor blood vessels by applying superb microvascular imaging (SMI) to contrast-enhanced ultrasonography (CEUS). A man in his 80s with a borderline resectable hepatocellular carcinoma received preoperative therapy using lenvatinib. The patient achieved a complete response after lenvatinib therapy, underwent hepatectomy, and maintained a cancer-free status. CEUS and SMI revealed a decrease in tumor blood vessels at 1 week after lenvatinib administration and a decrease in tumor perfusion at 2 weeks. Although CEUS alone is adequate for noninvasive real-time evaluation of tumor perfusion, it is not sufficient to achieve accurate assessments of tumor blood vessels. We performed a noninvasive time-course evaluation of vascular normalization after lenvatinib administration by applying SMI. The evaluation of vascular normalization with lenvatinib therapy using CEUS and SMI can support the decision to proceed to conversion therapies.

Abstract 5389: Development of T-cell exclusion in melanoma

Abstract Immune checkpoint inhibitors (ICIs), which prevent immune cell exhaustion and boost an antitumor response, have shown remarkable treatment efficacy in patients with advanced melanoma. However, its efficacy is limited by the emergence of resistance associated with an immunosuppressive tumor microenvironment (TME). The contribution of abnormal tumor vasculature to limited immune cell infiltration into the tumor core has been reported but the mechanisms of its development are still elusive. We analyzed how tumor angiogenesis affects the immune cell exclusion at different time points of primary melanoma using syngeneic murine melanomas. The spatial distribution of various immune cell populations and vascular integrity were analyzed in whole tumor cross-sections via multiplex immunofluorescence staining. We found that the exclusion pattern of CD8+ T cells was less evident with a balanced distribution across the whole tumor regions at the early stage. However, as the tumor grows, there is a pronounced accumulation of CD8+ T cells at the tumor periphery with a conspicuous absence in the core. Tumor blood vessels were structurally uniform and functionally stable in the early developmental tumor but became unstable and leaky as the tumor progressed, which was associated with the development of CD8+ T-cell exclusion. To understand the mechanism underlying vascular regulation of immune exclusion during tumor progression, we will investigate the expression of genes related to tumor angiogenesis using spatial transcriptomic analysis and RNA sequencing of endothelial cells (CD45+CD31-) sorted from the murine melanomas. These results highlight the contribution of spatial tumor vascular destabilization to the T-cell exclusion development, implying the potential of targeting tumor vasculature to enhance immune activation and the therapeutic efficacy of ICI in melanoma. Citation Format: Ha-Ram Park, Hee Won Yang, Minah Kim. Development of T-cell exclusion in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5389.

Abstract 7487: Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal cancer

Abstract Even in modern times when medical technology has advanced, cancer remains a life-threatening disease, and recurrence and metastasis are major issues in cancer treatment. The characteristics of cancer cells change with progression and treatment. Therefore, timely evaluation on their characteristics and decision on the treatment strategy are required. Circulating tumor cells (CTCs) are released into blood vessels in solid tumors and promote metastasis by circulating in the blood. CTCs are thus attractive targets for liquid biopsy and can provide useful information for selection of appropriate treatment. To obtain reliable results from CTC testing, it is important to prove that the detected cells are derived from cancerous tissue. In molecular tests targeting CTCs, it is still unclear whether the detected cells are derived from cancer tissue displaying genetic mutations. Aiming to establish reliable CTC testing, we have developed a simple method using molecular imaging flow cytometry to detect APC gene mutation together with Cytokeratin and Vimentin, which are epithelial-mesenchymal transition markers. Since, abnormalities in the APC gene are detected in 60-70% of colorectal cancer patients, detecting such mutations provides strong evidence that the detected cells are derived from cancerous tissue. Here, we show that upon evaluation of analytical performance of our method using cells isolated from cancerous tissue, our method showed high concordance rate against APC gene mutation. A clinical proof-of-concept using 5 mL of whole blood from colorectal cancer patients revealed that counts of cells with APC mutation in blood and cells with Cytokeratin and/or Vimentin expression in blood are highly correlated. Our results demonstrated a pathological stage-dependent increase in the count and frequency of Cytokeratin and/or Vimentin positive CTCs. We believe that our study not only establishes a practical approach for identifying CTCs in cancer patients but also provides potential implications in clinical practice, prognostic evaluation, and selection of treatment strategies. Citation Format: Yusuke Takahashi, Yuichi Ijiri, Shiki Fujino, Nakhaei Elnaz, Ayuko Kishimoto, Kentaro Shirai, Shigeki Iwanaga, Masatoshi Yanagida, Ali Asgar Bhagat, Norikatsu Miyoshi. Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7487.

Abstract 5402: Understanding the role of exercise in lymphatic vessel regulation in melanoma

Abstract Exercise has been demonstrated to be an effective method to remodel tumor blood vessels and to improve immune cell infiltration in multiple tumor models in mice. However, it is unclear whether aerobic exercise alters lymphatic vasculature in tumors. The lymphatic system plays an important role in tumor growth and metastasis because it regulates interstitial fluid pressure via lymph flow and immune cell trafficking, in conjunction with blood vessels. Lymphatic vessels are particularly important during metastasis because tumor cells frequently escape the primary tumor through lymphatic vasculature to establish the first site of metastasis in the lymph nodes. Here, we evaluated the effect of aerobic exercise on lymphatic vessels and lymphatic endothelial cell junctions in melanoma in male C57BL/6J mice. BP melanoma cells derived from transgenic mice with BrafV600E/+ and Pten−/− mutations were injected subcutaneously. Mice were assigned to no exercise and exercise groups when tumors reached ~30 mm3. The exercise group completed treadmill running at 12 meters/minute for 45 minutes for 5 consecutive days with 2 days of rest per week for 2 weeks before tumor harvest. Tumor lymphatic endothelial cells were identified by LYVE-1, endothelial tight junctions by ZO-1, and nuclei were identified by DAPI using immunofluorescence staining on frozen tumors. The number of total lymphatic vessels, elongated vessels( >100 µm), open lumens, and co-localization of ZO-1 with LYVE-1 was quantified on 6 random images per tumor using NIH Image J software. ANOVA and t-test were used to conduct statistical analysis (p < 0.05). Tumors from exercised mice had higher lymphatic vessel density (p=0.002) and more open lumens (p=0.001). Surprisingly, tumors from exercised mice had fewer ZO-1 positive vessels (p=0.015) and lower co-localization of ZO-1 and LYVE-1 (p = 0.0185) than tumors from non-exercised mice, suggesting fewer stable endothelial cell junctions in lymphatic vessels. The higher lymphatic vessel density and higher number of open lumens present in tumors from exercised mice may contribute to an exercise-induced improved anti-tumor immune response, which has been previously reported. However, the lower ZO-1 expression on lymphatic endothelial cells in tumors from exercised mice may indicate lymphatic vasculature dysfunction and/or hyper-permeability. Further work is needed to assess the functional changes in tumor lymphatic vasculature by exercise, and how these changes impact the anti-tumor immune response and metastasis. Citation Format: Priya Tirumala, Jonghae Lee, Keri L. Schadler. Understanding the role of exercise in lymphatic vessel regulation in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5402.

Abstract 6659: Oncolytic herpes simplex virus expressing XCL1 and FLT3L modulate the intratumoral immune response and improve the anti-tumor efficacy in a metastatic breast tumor model

Abstract Patients with metastatic breast cancer (MBC) have a dismal prognosis, with a 5-year survival rate of only 26%. The inadequate infiltration of immune cells targeting the tumor microenvironment (TME) is a key factor contributing to this low survival rate. Immune effector cells, including CD8+ cytotoxic T cells, NKT cells, and NK cells, play a crucial role in targeting tumor cells. The activation of immune effector cells relies on the presence of conventional type I dendritic cells (cDC1), which present tumor-specific antigenic peptides on their surface. Recent studies have identified the chemokine XCL1 and growth factor FLT3L as critical factors involved in the intratumoral recruitment and expansion of dendritic cells. To enhance the activity of cDC1 in the TME we designed an oncolytic herpes simplex virus (oHSV) expressing XCL1 and FLT3L. The recombinant oHSV, rQ1-XF, was generated by incorporating LoxP sites into the viral genome through recombination with a carrier plasmid carrying the polycistronic cassette. To enhance the intratumoral penetration of oHSV injected intravenously in primary tumors and MBC lesions in the lung, we employed the cancer drug ganetespib, which can increase the permeability of tumor blood vessels. In comparison to untreated mice, ganetespib combined with rQ1-XF reduced the size of primary tumors and induced a short but significant increase in the survival of mice. Additionally, compared to the ganetespib alone treatment, ganetespib combined with rQ1-XF reduced MBC burden in the lung. The flow cytometry analysis of immune cells revealed an increased infiltration of CD11c+CD11b- dendritic cells in primary tumors treated with oHSV combination therapy compared to the ganetespib only control. A similar trend was also observed in CD4 T cells and CD8 T cells in primary tumors. As expected, there was a negative correlation between tumor burden and the infiltration of CD4+ T cells and CD8+ T cells in primary tumors. Ganetespib combined with oHSV also reduced the infiltration of CD4+ regulatory T cells (Tregs) in primary tumors, however the number of Tregs increased with primary tumor size as well as tumor burden in the lung. This could potentially lead to reduced efficacy of tumor-infiltrating dendritic cells in activating effector T cells in tumors treated with ganetespib and rQ1-XF. Moreover, the combination therapy did not yield significant alterations in the populations of DCs, CD4+ T cells, and CD8+ T cells in lungs with metastatic lesions. Further studies are underway to investigate whether the depletion of Treg cells in combination with rQ1-XF enhances effector T cell activation against metastatic breast tumor cells. The findings of this study will provide valuable insights into the effectiveness of using XCL1 and FLT3L-armed oncolytic viruses in patients with MBC. Citation Format: Himanshu Soni, Liqun Gu, Sylvie Roberge, Heena Kumra, Hiroshi Nakashima, E. Antonio Chiocca, Yves Boucher. Oncolytic herpes simplex virus expressing XCL1 and FLT3L modulate the intratumoral immune response and improve the anti-tumor efficacy in a metastatic breast tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6659.

Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Intraosseous cavernous hemangioma of parietal bone: A case report and literature review

Introduction and background: Intraosseous Hemangiomas or Primary Intraosseous Hemangiomas (PIH) are slow-growing innocuous blood vessel tumors that make up less than 1% of all bone malignancies [1]. These lesions are estimated to account for 0.2 percent of all benign skull tumors [4], with a clear female predisposition (3:1) [2]. Prior trauma to the region is thought to be the most prevalent cause of intraosseous hemangiomas. They bleed profusely when removed or biopsied; therefore, preoperative diagnosis of the lesion’s vascular character is critical [8]. They are most frequently seen in the vertebral skeleton, although they can also be found in the calvarium and facial bones. The temporal bone is the most prevalent place in the head after the vertebral skeleton, followed by the parietal, mandible, malar, and zygomatic areas [8]. In this case report, we discuss the case of a 9-year-old male who presented with a large soft mass in his right parietal region.

A review of ultrasound contrast media.

Efforts have been made over the last five decades to create effective ultrasonic contrast media (UCM) for cardiac and noncardiac applications. The initial UCM was established in the 1980s, following publications from the 1960s that detailed the discovery of ultrasonic contrast enhancement using small gaseous bubbles in echocardiographic examinations. An optimal contrast agent for echography should possess the following characteristics: non-toxicity, suitability for intravenous injection, ability to traverse pulmonary, cardiac, and capillary circulations, and stability for recirculation. Definity, Optison, Sonazoid, and SonoVue are examples of current commercial contrast media. These contrast media have shown potential for various clinical reasons, both on-label and off-label. Several possible UCMs have been developed or are in progress. Advancements in comprehending the physical, chemical, and biological characteristics of microbubbles have significantly improved the visualization of tumor blood vessels, the identification of areas with reduced blood supply, and the enhanced detection of narrowed blood vessels. Innovative advances are expected to enhance future applications such as ultrasonic molecular imaging and therapeutic utilization of microbubbles.

Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors, and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression. Herein, we demonstrated that salvianic acid A (SAA) played a pivotal role in contributing to vascular normalization in the tumor-bearing mice, thereby improving delivery and effectiveness of the chemotherapeutic agent. SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells (HUVECs) exposed to hypoxia. Mechanistically, SAA was inclined to directly bind to the glycolytic enzyme PKM2, leading to a dramatic decrease in endothelial glycolysis. More importantly, SAA improved the endothelial integrity via activating the β-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner. Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

Transmembrane modification of tumor vascular targeting peptide A7R as molecular cargo delivery tool

In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 μmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

Computational design of anti-cancer peptides tailored to target specific tumor markers

Anti-cancer peptides (ACPs) are short peptides known for their ability to inhibit tumor cell proliferation, migration, and the formation of tumor blood vessels. In this study, we designed ACPs to target receptors often overexpressed in cancer using a systematic in silico approach. Three target receptors (CXCR1, DcR3, and OPG) were selected for their significant roles in cancer pathogenesis and tumor cell proliferation. Our peptide design strategy involved identifying interacting residues (IR) of these receptors, with their natural ligands serving as a reference for designing peptides specific to each receptor. The natural ligands of these receptors, including IL8 for CXCR1, TL1A for DcR3, and RANKL for OPG, were identified from the literature. Using the identified interacting residues (IR), we generated a peptide library through simple permutation and predicted the structure of each peptide. All peptides were analyzed using the web-based prediction server for Anticancer peptides, AntiCP. Docking simulations were then conducted to analyze the binding efficiencies of peptides with their respective target receptors, using VEGA ZZ and Chimera for interaction analysis. Our analysis identified HPKFIKELR as the interacting residues (IR) of CXCR-IL8. For DcR3, we utilized three domains from TL1A (TDSYPEP, TKEDKTF, LGLAFTK) as templates, along with two regions (SIKIPSS and PDQDATYP) from RANKL, to generate a library of peptide analogs. Subsequently, peptides for each receptor were shortlisted based on their predicted anticancer properties as determined by AntiCP and were subjected to docking analysis. After docking, peptides that exhibited the least binding energy were further analyzed for their detailed interaction with their respective receptors. Among these, peptides C9 (HPKFELY) and C7 (HPKFEWL) for CXCR1, peptides D6 (ADSYPQP) and D18 (AFSYPFP) for DcR3, and peptides P19 (PDTYPQDP) and p16 (PDQDATYP) for OPG, demonstrated the highest affinity and stronger interactions compared to the other peptides. Although in silico predictions indicated a favorable binding affinity of the designed peptides with target receptors, further experimental validation is essential to confirm their binding affinity, stability and pharmacokinetic characteristics.

Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin β4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.

Spatial Transcriptomics in a Case of Follicular Thyroid Carcinoma Reveals Clone-Specific Dysregulation of Genes Regulating Extracellular Matrix in the Invading Front

Follicular thyroid carcinoma (FTC) is recognized by its ability to invade the tumor capsule and blood vessels, although the exact molecular signals orchestrating this phenotype remain elusive. In this study, the spatial transcriptional landscape of an FTC is detailed with comparisons between the invasive front and histologically indolent central core tumor areas. The Visium spatial gene expression platform allowed us to interrogate and visualize the whole transcriptome in 2D across formalin-fixated paraffin-embedded (FFPE) tissue sections. Four different 6 × 6 mm areas of an FTC were scrutinized, including regions with capsular and vascular invasion, capsule-near area without invasion, and a central core area of the tumor. Following successful capturing and sequencing, several expressional clusters were identified with regional variation. Most notably, invasive tumor cell clusters were significantly over-expressing genes associated with pathways interacting with the extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition (EMT). Subsets of these genes (POSTN and DPYSL3) were additionally validated using immunohistochemistry in an independent cohort of follicular thyroid tumors showing a clear gradient pattern from the core to the periphery of the tumor. Moreover, the reconstruction of the evolutionary tree identified the invasive clones as late events in follicular thyroid tumorigenesis. To our knowledge, this is one of the first 2D global transcriptional mappings of FTC using this platform to date. Invasive FTC clones develop in a stepwise fashion and display significant dysregulation of genes associated with the ECM and EMT — thus highlighting important molecular crosstalk for further investigations.

The augmentation of cytotoxic immune cell functionality through physical exertion bolsters the potency of chemotherapy in models of mammary carcinoma.

Mammary carcinoma, a pervasive and potentially lethal affliction, is conjectured to be profoundly influenced by physical exercise, both in prophylaxis and therapeutic contexts. This study endeavors to explore the repercussions of exercise training on the progression of mammary carcinoma, particularly the mechanisms by which the amalgamation of an exercise regimen and doxorubicin induces tumor cell apoptosis. Female BALB/c mice were categorized into four distinct groups: A sedentary group (SED), an exercise group (Ex), a doxorubicin group (Dox, 5 mg/kg), and a combined treatment group (Dox + Ex). The exercise training lasted for 21 days and included aerobic rotarod exercise and resistance training. The impact of exercise training on tumor growth, immune cell proportions, inflammatory factor levels, and cell apoptosis pathway was assessed. Exercise training significantly curtailed tumor growth in a mouse model of breast cancer. Both the Ex and Dox groups exhibited significant reductions in tumor volume and weight (p < 0.01) in comparison to the SED group, while the Dox + Ex group had a significantly lower tumor volume and weight than the Dox group (p < 0.01). Exercise training also significantly increased the proportion of NK and T cells in various parts of the body and tumor tissue, while decreasing tumor blood vessels density. Exercise training also increased IL-6 and IL-15 levels in the blood and altered the expression of apoptosis-related proteins in tumor tissue, with the combined treatment group showing even more significant changes. Physical training improves the effectiveness of doxorubicin in treating breast cancer by activating cytotoxic immune cells, releasing tumor suppressor factors, and initiating mt-apoptosis, all while mitigating the adverse effects of chemotherapy.

The Inhibition of Vessel Co-Option as an Emerging Strategy for Cancer Therapy.

Vessel co-option (VCO) is a non-angiogenic mechanism of vascularization that has been associated to anti-angiogenic therapy. In VCO, cancer cells hijack the pre-existing blood vessels and use them to obtain oxygen and nutrients and invade adjacent tissue. Multiple primary tumors and metastases undergo VCO in highly vascularized tissues such as the lungs, liver or brain. VCO has been associated with a worse prognosis. The cellular and molecular mechanisms that undergo VCO are poorly understood. Recent studies have demonstrated that co-opted vessels show a quiescent phenotype in contrast to angiogenic tumor blood vessels. On the other hand, it is believed that during VCO, cancer cells are adhered to basement membrane from pre-existing blood vessels by using integrins, show enhanced motility and a mesenchymal phenotype. Other components of the tumor microenvironment (TME) such as extracellular matrix, immune cells or extracellular vesicles play important roles in vessel co-option maintenance. There are no strategies to inhibit VCO, and thus, to eliminate resistance to anti-angiogenic therapy. This review summarizes all the molecular mechanisms involved in vessel co-option analyzing the possible therapeutic strategies to inhibit this process.