Search Results (51)

Background/Objectives: Colorectal cancer (CRC) is the second most common cancer-causing death in the United States. The Mediterranean diet, rich in extra-virgin olive oil (EVOO), is associated with a lower risk of colorectal cancer (CRC). Earlier studies reported S-(−)-oleocanthal (OC), the major EVOO phenolic, to be effective in CRC progression and recurrence suppression in a subcutaneous xenograft model by targeting the SMYD2–EZH2/c-MET signaling axis and favorably modulating gut microbiota (GM). However, lead validation in an orthotopically xenografted model that mimics the tumor microenvironment is yet to be achieved. The GM contribution to OC anti-CRC activity remains unknown. Methods: We used an orthotopic intra-cecally xenografted nude mouse model to validate OC anti-KRAS-mutant CRC activity and assessed the contribution of OC GM modulation to this activity using an oral antibiotic depletion strategy. Results: Daily oral 10 mg/kg OC impressively suppressed KRAS^G13D-mutant CRC HCT-116-Luc progression and metastasis more effectively than intraperitoneal administration 3×/week. By contrast, GM depletion with a broad-spectrum antibiotics cocktail (ABC) partially attenuated this activity, suggesting GM contribution to OC anti-CRC activity. Thus, fecal microbiota transplantation (FMT) was conducted using fresh daily oral fecal GM treatments collected from 20 mg/kg OC-dosed nude mouse donors. A week before FMT dosing, orthotopic HCT-116-Luc tumor-bearing recipient mice were subjected to GM depletion using daily oral ABC dosing. Recipient mice treated with FMT from OC-treated donors exhibited dramatic >99% reductions in primary and near-complete suppression of multi-organ metastatic tumor burden versus FMT controls. Conclusions: Collectively, oral OC is validated as an effective anti-KRAS^G13D-mutant CRC lead. Future clinical trials can validate its anti-CRC potential in a human model. Full article

Background: The aggressive progression of mesothelioma is driven not only by intrinsic tumor cell plasticity but also by dynamic interactions between tumor cells and the surrounding stromal microenvironment; however, the mechanisms by which stromal populations regulate epithelial–mesenchymal transition (EMT), tumor evolution, and therapeutic resistance remain unclear. Methods: We integrated longitudinal transcriptomic profiling with single-cell RNA sequencing in a murine intraperitoneal mesothelioma model spanning disease progression from week 0 to week 8 to identify stromal-EMT programs associated with tumor progression. In vitro fibroblast–tumor co-culture systems were used to assess how different fibroblast-to-tumor cell ratios influence transcriptional reprogramming and mesenchymal transition. Results: Single-cell analysis revealed marked stromal heterogeneity, identifying eight distinct cancer-associated fibroblast (CAF) subtypes: myCAF, mCAF, iCAF, TGF-βCAF, vCAF, plCAF, apCAF, and meCAF. These subsets showed specialized transcriptional programs associated with developmental signaling and metabolic adaptation. Functional analyses demonstrated coordinated intercellular communication across six interconnected modules, including mesenchymal transition, fibrotic remodeling, TGF-β/metabolic adaptation, adhesion signaling, WNT activation, and inflammatory crosstalk. Notably, mCAF, TGF-βCAF, and plCAF populations showed transcriptional convergence, suggesting cooperative formation of a desmoplastic, immunoregulatory niche. Co-culture experiments confirmed that fibroblast-derived signaling induces ratio-dependent transcriptional changes, promoting a shift from epithelioid to mesenchymal phenotypes. Conclusions: These findings highlight stromal regulation of EMT as a key driver of mesothelioma progression, sarcomatoid transition, and therapy resistance, and identify tumor–stroma signaling networks as potential therapeutic targets. Full article

Background/Objectives: Peritoneal metastases (PMs) arise from gastrointestinal, gynecologic, hepatobiliary, and colorectal origins and are associated with poor outcomes. Cytoreductive surgery (CRS) with intraperitoneal (IP) chemotherapy offers benefit for select patients, but survival remains limited. This review aims to summarize recent insights into the molecular and tumor microenvironmental (TME) changes characteristic of PMs and the impact of IP chemotherapy. Methods: A literature review was performed using recent clinical, translational, and preclinical studies examining alterations in molecular signaling, DNA repair alterations, metabolic pathways, and angiogenic factors in PMs before and after IP therapy. Results: Peritoneal metastases exhibit distinct biology after being treated with IP chemotherapy. Treatment induces alterations in gene expression, mutational patterns, and immune infiltrates. Heated intraperitoneal chemotherapy (HIPEC) has been associated with increased CD8+ T-cell activity, macrophage and NK cell shifts, and modulation of PD-1/PD-L1 signaling, which correlate with treatment response and survival. Emerging data on PIPAC similarly suggests induction of favorable gene expression changes with repeated treatment, though supporting evidence remains more limited than for HIPEC. Angiogenic pathways—particularly VEGF and HIF1α—remain key drivers of PM progression and predictors of post-operative outcomes. Early findings suggest potential synergy between IP chemotherapy and immunotherapy though clinical trials are ongoing. Conclusions: IP chemotherapy induces tumor microenvironmental changes that have potential to shape therapeutic response. Characterizing these measurable biologic changes may allow clinicians to improve patient selection and support the development of combination therapies to enhance outcomes. Full article

For decades, peritoneal metastases (PM) have been regarded as a terminal manifestation of advanced malignancies and managed primarily with palliative intent because of limited sensitivity to systemic therapies. Accumulating clinical, molecular, and immunological evidence now supports the view that PM is not merely an anatomic pattern of spread but a distinct metastatic niche with characteristic biological, microenvironmental, and therapeutic features. This review summarizes the major routes of PM development—transcoelomic, lymphatic, and hematologic dissemination—and emphasizes how these pathways converge through shared biological programs. Core mechanisms include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. A central focus is the peritoneal tumor microenvironment: mesothelial-to-mesenchymal transition, cancer-associated fibroblast activity, adipocyte-derived metabolic support, macrophage polarization, and regulatory T-cell enrichment collectively shape an immunotolerant and treatment-resistant niche on the peritoneal surface. In addition, evidence from pre-metastatic niche biology suggests that primary tumor-derived exosomes and epitranscriptomic regulation can prime the peritoneal environment before overt implantation. These features provide a biological rationale for locoregional strategies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, as well as emerging intraperitoneal modalities and microenvironment-targeted approaches. Finally, organoid platforms, liquid biopsy-based minimal residual disease monitoring, and theranostic technologies may enable more personalized, biology-driven management of PM. Full article

Background: Epithelial ovarian cancer (EOC) is characterized by aggressive peritoneal dissemination and an immunosuppressive tumor microenvironment in which tumor-associated macrophages (TAMs) play a central role. Chemokine signaling pathways regulate macrophage recruitment and function; however, the contribution of the CX3CL1–CX3CR1 axis to ovarian cancer progression and TAM-mediated effector mechanisms remains unclarified. This study aimed to clarify the role of CX3CL1–CX3CR1 signaling in ovarian cancer progression, focusing on macrophage-derived pro-tumorigenic factors. Methods: CX3CL1 and CX3CR1 expression was examined in human EOC and healthy ovarian tissues by real-time polymerase chain reaction and immunohistochemistry. Functional effects of CX3CL1 on ovarian cancer cells were evaluated via migration and proliferation assays in the murine ID8 cell line. An intraperitoneal syngeneic ovarian cancer model was established by injecting ID8 cells into wild-type and Cx3cr1-deficient mice. Tumor burden, ascites formation, survival, macrophage infiltration, and expression levels of matrix metalloprotease-2 (MMP-2) and transforming growth factor-β (TGF-β) were assessed by histological, immunohistochemical, and molecular analyses. Results: CX3CL1 and CX3CR1 expression was significantly upregulated in human EOC tissues and associated with marked macrophage infiltration. CX3CL1 stimulation enhanced migration, but not proliferation, of ID8 cells. Cx3cr1 deficiency significantly suppressed intraperitoneal tumor growth, reduced ascitic fluid volume, and prolonged survival. This was accompanied by reduced CX3CR1⁺ TAM accumulation and decreased MMP-2 and TGF-β expression, which were predominantly produced by infiltrating macrophages. Conclusions: The CX3CL1–CX3CR1 axis promotes ovarian cancer progression by recruiting MMP-2- and TGF-β-producing macrophages. Targeting CX3CR1-dependent TAM functions may represent a therapeutic strategy for limiting peritoneal dissemination in ovarian cancer. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Our previous study demonstrated that combination therapy with local hyperthermia (HT) and anti-CTLA-4 antibody (C4), an immune checkpoint inhibitor, induced regression of both local and distant tumors. However, tumor microenvironment (TME) changes in local and distant tumors following local HT and C4 remain unclear. Here, we aimed to evaluate TME changes in local and distant tumors induced by local HT + C4 therapy. Methods: Murine TNBC cells were inoculated in both legs of male BALB/cAJcl mice, and only one leg was treated with HT (42.5 °C for 20 min). C4 was administered intraperitoneally every 3 days for a total of 3 doses. For CD4⁺ T cell depletion experiments, anti-CD4 antibody (αCD4) was administered intraperitoneally every 3 days for a total of 12 doses. Tumor-infiltrating immune cells in locally heated tumors and unheated distant tumors were analyzed 9 days after the initial treatment. Furthermore, tumor growth in heated tumors and unheated distant tumors under αCD4 administration was evaluated. Results: HT + C4 therapy increased the proportion of helper T cells and elevated the ratio of cytotoxic T cells plus helper T cells to myeloid-derived suppressor cells in both heated tumors and unheated distant tumors. The HT + C4 + αCD4 group exhibited significantly larger tumor growth, compared with the HT + C4 group in both heated (p < 0.01) and unheated distant tumors (p < 0.01). Conclusions: These results suggest that combination therapy of HT and C4 favorably modulates the TME. CD4⁺ T cell infiltration may contribute to both local and distant antitumor effects. Full article

Background/Objectives: Peritoneal metastases (PMs) remain difficult to treat because the peritoneum–plasma barrier limits drug penetration from the systemic circulation. Intraperitoneal chemotherapy (IPC), particularly repeated intraperitoneal (IP) administration via implantable ports, can achieve high local drug exposure with prolonged retention. This review summarizes the pharmacological rationale, clinical evidence, and future directions of catheter-based IPC, with emphasis on combined IP and systemic chemotherapy for ovarian, gastric, and pancreatic cancers. Methods: We narratively reviewed prospective clinical trials and key retrospective studies evaluating IPC and compared repeated catheter-based IPC with hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). Efficacy, safety, practice considerations, and opportunities for ascites-based monitoring were examined. Results: In ovarian cancer, several randomized trials demonstrated improved progression-free survival (PFS), and in selected trials, improved overall survival (OS) was demonstrated using IP plus intravenous (IV) therapy, although in the latter trials, toxicity and catheter-related complications limited treatment completion. A phase III Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial further showed significantly prolonged PFS with IP carboplatin and weekly paclitaxel, with non-catheter-related toxicity comparable to that of IV therapy. In gastric and pancreatic cancer, phase II studies reported symptomatic control, cytologic conversion, and higher rates of conversion surgery in selected patients, although confirmatory phase III data are limited. Device complications, including infection, obstruction, and leakage, occurred, but were manageable. Conclusions: Repeated catheter-based IPC is a feasible approach that enhances intraperitoneal drug delivery and complements IV chemotherapy. Future priorities include randomized trials, pharmacokinetic optimization, and biomarker-guided patient selection, supported by serial ascites assessment to refine indications and improve outcomes. Full article

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored. Methods: To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation. Results: In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages. Conclusions: Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer Full article

High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell–cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy. Full article

Background/Objectives: Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of several types of cancers. In this study, we assess treatment efficacy for metastatic and immunosuppressive pancreatic cancer. Methods: Orthotopic mouse models were generated by injection of tumor cells into the pancreatic parenchyma. Sindbis vectors were inoculated intraperitoneally. Imaging of tumors was performed by either MRI or in vivo imaging using luciferase. Flow cytometry, multi-immunofluorescence and elispot analysis were performed for certain tumors. Results: SV can infect and reduce pancreatic tumors in three mouse model systems: a model bearing human pancreatic tumors, a highly metastatic model, and a model that reflects the highly immunosuppressive, desmoplastic microenvironment common to human pancreatic cancer. Conclusions: Combination of SV vector expressing IL12 with an immune co-stimulatory agent, anti-OX40, can reduce tumors, facilitate an influx of immune response cells into the tumor microenvironment, and prevent tumors in mice rechallenged with tumor cells promising an effective treatment for pancreatic cancer. Full article

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy. Full article

Tumor-associated macrophages (TAMs) in the colorectal cancer (CRC) microenvironment promote tumor progression but can be reprogrammed into a pro-inflammatory state with anti-cancer properties. Activation of the G protein-coupled receptor 84 (GPR84) is associated with pro-inflammatory macrophage polarization, making it a potential target for CRC therapy. This study evaluates the effects of the GPR84 agonists 6-OAU and ZQ-16 on macrophage activation and anti-cancer efficacy. GPR84 expression on THP-1 macrophages and murine BMDMs was analyzed using flow cytometry. Macrophages were treated with 6-OAU or ZQ-16, and pro-inflammatory cytokine levels, reactive oxygen species (ROS) production, and phagocytosis were assessed using qPCR and functional assays. Anti-cancer effects were tested in a subcutaneous MC38 tumor model, with oral or intraperitoneal agonist administration. Pharmacokinetics and compound stability were also evaluated. In THP-1 macrophages, 6-OAU increased pro-inflammatory cytokines and ROS production, with ZQ-16 showing similar effects. However, neither agonist induced pro-inflammatory responses, ROS production, or phagocytosis in murine macrophages. In vivo, both agonists failed to inhibit tumor growth in the MC38 model despite systemic exposure. Current GPR84 agonists lack efficacy in promoting anti-cancer macrophage activity, limiting their potential as CRC therapies. Full article

Murine xenograft models are valuable and increasingly used preclinical tools in cancer research to understand disease pathogenesis and guide treatment options. The aim of this narrative review is to summarize the studies that employed mouse xenograft models, using cell lines, patient-derived tumors, or organoids, in endometrial cancer (EC) research, detailing their methodology and main findings. We identified 27 articles reporting on heterotopic EC xenografts, including subcutaneous, subrenal capsule, intraperitoneal, and retro-orbital models, and 18 articles using orthotopic xenografts. Subcutaneous xenografts generated using either cell lines or patient tumors have been widely used; however, their low engraftment rates and the inability to recapitulate main clinical features such as metastases limit their translational value. Subrenal capsule models showed improved engraftment rates compared to subcutaneous models, but tumors exhibited slower and constrained tumor growth. Orthotopic models are technically more challenging to generate and monitor, but tumor growth occurs in a relevant microenvironment and EC ortho-xenografts exhibit high engraftment rates and metastases to clinically relevant sites. Cell line-based xenograft (CDX) models are attractive tools because they are convenient, easy to use, and amenable to genetic modifications, making them suitable for proof-of-concept approaches and large-scale studies. EC xenografts developed from patient tumors (PDTXs) are more labor/cost-intensive for their establishment but can capture the genetic and molecular heterogeneity within and across histologic subtypes and can inform personalized patient treatment. EC organoid-based xenograft (PDOX) models combine the advantages of both CDXs and PDTXs since they are more time- and cost-effective, faithfully maintain tumor characteristics and therapeutic responses, and can be genetically modified. Despite substantial progress in EC management, there are still several unmet needs. Efficient targeted treatments are currently indicated only for a small subgroup of patients, while women with recurrent or advanced-stage EC have very few therapeutic options and their prognosis remains unfavorable. Novel (targeted) drugs, combinational regimens and tools to predict the real drug response in patients are urgently needed. Xenograft models are expected to inform about disease mechanisms and to help identify novel therapeutic options and suitable target patients. Full article

Lipopolysaccharides (LPSs) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression with epidermal growth factor receptor (EGFR) expression in the tumor microenvironment. We used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by a reverse transcription polymerase chain reaction revealed higher vascularization, with increased interleukin-8 (IL-8) expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only the tumor cell growth and migration/invasion of EGFR-positive HCC cells but also tumor neovascularization via IL-8 signaling. Full article

High-grade serous ovarian cancer (HGSOC) is one of the most lethal tumors generally and the most fatal cancer of the female genital tract. The approved standard therapy consists of surgical cytoreduction and platinum/taxane-based chemotherapy, and of targeted therapy in selected patients. The main therapeutic problem is chemoresistance of recurrent and metastatic HGSOC tumors which results in low survival in the group of FIGO III/IV. Therefore, the prediction and monitoring of chemoresistance seems to be of utmost importance for the improvement of HGSOC management. This type of cancer has genetic heterogeneity with several subtypes being characterized by diverse gene signatures and disturbed peculiar epigenetic regulation. HGSOC develops and metastasizes preferentially in the specific intraperitoneal environment composed mainly of fibroblasts, adipocytes, and immune cells. Different HGSOC subtypes could be sensitive to distinct sets of drugs. Moreover, primary, metastatic, and recurrent tumors are characterized by an individual biology, and thus diverse drug responsibility. Without a precise identification of the tumor and its microenvironment, effective treatment seems to be elusive. This paper reviews tumor-derived genomic, mutational, cellular, and epigenetic biomarkers of HGSOC drug resistance, as well as tumor microenvironment-derived biomarkers of chemoresistance, and discusses their possible use in the novel complex approach to ovarian cancer therapy and monitoring. Full article