Search Results (23)

Glioblastoma (GBM) recurs predominantly from infiltrative disease that persists beyond the contrast-enhancing tumor (CET). This structured narrative review aims to define the invasive margin and peritumoral brain zone (PBZ) as a spatially organized molecular ecosystem, summarize the approaches used to interrogate this compartment, and evaluate how malignant-cell plasticity, host niches, and treatment-induced remodeling contribute to minimal residual disease and recurrence. A structured literature search of PubMed/MEDLINE, Scopus, and Web of Science identified the clinical, translational, preclinical, and review literature available through July 2026; evidence was synthesized qualitatively, with priority given to human tissue studies and single-cell or spatially resolved analyses. Across studies, the margin differs from both tumor core and normal brain and contains heterogeneous malignant states interacting with neural, vascular, immune, hypoxic, and extracellular-matrix-supported niches. Surgery, radiotherapy, and systemic treatment further reshape these interactions through inflammation, vascular injury, senescence, hypoxia, and fibrosis. The main translational challenge is therefore not simply to control the CET, but to identify biologically high-risk non-enhancing tissue and demonstrate that therapy reaches and modifies it. We propose three priorities: image-registered characterization of residual compartments, regional measurement of drug exposure and target engagement, and integration of local margin control with distributed and niche-directed treatment. Prospective validation is required before spatial PBZ biomarkers can guide routine care. Full article

Background/Objectives: Renal cell carcinoma (RCC) is a common and often asymptomatic malignancy with limited treatment options for advanced stages. Chronic inflammation and cellular senescence—collectively termed “inflammaging”—are emerging as key contributors to tumor progression. This study aimed to investigate the expression of inflammaging-related markers in RCC tissues, focusing on the role of PTX3, IL-6, and senescence-associated proteins in the tumor microenvironment. Methods: A retrospective cohort of 57 patients with clear cell RCC who underwent nephrectomy was analyzed. Formalin-fixed paraffin-embedded samples from tumor, peritumoral, and normal renal tissues were examined using confocal immunofluorescence microscopy to assess PTX3, IL-6, p21, and p16 expression. Senescence-associated β-galactosidase staining was performed to identify senescent cells. Serum IL-6 levels were measured by ELISA, and survival analysis was conducted using Kaplan–Meier curves and Cox regression analysis. Results: PTX3 and IL-6 were significantly upregulated in both peritumoral and tumor tissues compared to normal kidney samples (p < 0.001). Expression of senescence markers p21 and p16 were elevated in peritumoral areas (p < 0.001) as compared to normal renal tissues, but their expression was reduced or absent in the tumor core. High-grade and high-stage tumors exhibited stronger PTX3 and IL-6 expression and lower levels of cell cycle inhibitors (p < 0.001). Patients with elevated serum IL-6 levels had significantly lower 5-year cancer-specific survival (p < 0.005) and shorter progression-free survival (p < 0.001). Conclusions: Our findings suggest that peritumoral tissue in RCC exhibits a senescent and proinflammatory phenotype that may support tumor progression. PTX3 and IL-6 are potential biomarkers of disease severity and prognosis. Targeting inflammaging pathways could offer new therapeutic strategies for RCC, particularly in aggressive disease forms. Full article

For decades, cancer risk has been explained mainly by local factors. However, emerging evidence shows that the oral microbiome acts as a systemic modifier of oncogenesis well beyond the head and neck. This review synthesizes clinical and mechanistic data linking dysbiotic oral communities, especially Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, to malignancies across gastrointestinal, respiratory, hepatobiliary, pancreatic, breast, and urogenital systems. We summarize organ-specific associations from saliva, tissue, and stool studies, noting the recurrent enrichment of oral taxa in tumor and peri-tumoral niches of oral, esophageal, gastric, colorectal, lung, pancreatic, liver, bladder, cervical, and breast cancers. Convergent mechanisms include the following: (i) persistent inflammation (lypopolysacharide, gingipains, cytolysins, and collagenases); (ii) direct genotoxicity (acetaldehyde, nitrosation, and CDT); (iii) immune evasion/suppression (TLR/NLR signaling, MDSC recruitment, TAN/TAM polarization, and TIGIT/CEACAM1 checkpoints); and (iv) epigenetic/signaling rewiring (NF-κB, MAPK/ERK, PI3K/AKT, JAK/STAT, WNT/β-catenin, Notch, COX-2, and CpG hypermethylation). Plausible dissemination along an oral–gut–systemic axis, hematogenous, lymphatic, microaspiration, and direct mucosal transfer enables distal effects. While causality is not yet definitive, cumulative data support oral dysbiosis as a clinically relevant cofactor, motivating biomarker-based risk stratification, saliva/stool assays for early detection, and microbiome-targeted interventions (periodontal care, antimicrobials, probiotics, and microbiota modulation) alongside conventional cancer control. Full article

Background: Mast cells, key effectors of the innate immune system, are known to participate in various stages of tumor progression, including inflammation, angiogenesis, and extracellular matrix remodeling. Their role in melanoma, particularly in relation to Breslow thickness, pT stage, and AJCC staging, remains unclear. This study aims to quantitatively and phenotypically assess mast cell infiltration in cutaneous melanoma at different stages of progression, focusing on Tryptase- and Chymase-positive subtypes. Methods: This retrospective multicenter study included 124 patients with cutaneous melanoma (AJCC 8th edition, stages IA–IIIC). Histological sections were stained with hematoxylin and eosin, and mast cells were visualized using toluidine blue and immunohistochemistry with anti-Tryptase and anti-Chymase antibodies. Mast cells were counted manually in intratumoral and peritumoral regions by two independent observers. Quantitative data were analyzed using non-parametric tests and presented as median [Q1–Q3]. Results: Histological examination of 124 melanoma samples confirmed typical features of cutaneous melanoma, with nodular melanoma being the most common subtype (68 cases, 54.8%) and the lower extremities identified as the predominant tumor location (47 cases, 37.9%). Toluidine blue staining verified the presence of mast cells in both intratumoral and peritumoral compartments, with the highest density observed in early-stage melanomas. Immunohistochemical analysis identified both Tryptase+ and Chymase+ mast cells. The intratumoral number of Tryptase+ cells declined from 17 [14–19] per HPF at AJCC stage IA to 6 [5–7] per HPF at stage IIIC, while Chymase+ mast cells decreased from 14 [11–16] per HPF to 2 [1–3] per HPF over the same stages. Peritumoral counts also showed a downward trend, although less pronounced. Overall, the most significant reduction was observed in Chymase+ mast cells, suggesting their potential role as markers of melanoma progression. Conclusions: This study highlights the dynamic changes in mast cell populations in cutaneous melanoma, with a pronounced decrease in Chymase⁺ mast cells as the tumor progresses. Further research is needed to explore the mechanistic role of mast cells and their phenotypic shifts in melanoma progression. Full article

Red meat consumption is considered a risk factor for colorectal cancer (CRC) development and stimulated isolation of plasmid-like DNA molecules from bovine serum and milk, termed bovine meat and milk factors (BMMFs). BMMFs encode a conserved replication protein (Rep). Increased populations of Rep-expressing macrophages have been identified in the peritumor of CRC patients and pre-cancerous tissues when compared to the tissues of healthy individuals. This supports the concept that BMMFs increase cancer risk by indirect carcinogenesis, upon induction of chronic inflammation. However, the spread of Rep⁺ immune cells in tissues at greater distances from primary tumors has not yet been assessed. Here, we immunohistologically analyzed the presence of Rep⁺ immune cells in sets of tumor, peritumor and, additionally, distant tissues of CRC patients (n = 13). We identified consistently high numbers of BMMF-positive macrophages in mucosal tissues at distances of as much as 25 cm away from the primary tumors, at levels comparable to peritumors and associated with M2-like macrophage polarization. The broad distribution of BMMFs suggests that BMMF⁺ macrophages might already exist at stages of pre-cancerous dysplasia or before. Quantification of BMMF tissue expression during colonoscopy might help to preventively stratify individuals at risk of developing polyps/CRC and recommend them for enhanced surveillance and/or changes in dietary lifestyle. Full article

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16–24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusions: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG. Full article

In canine mammary neoplasms, greater inflammation is associated with higher histological grade, lymphatic invasion, and metastases. This retrospective study assessed the density of peri- and intratumoral tumor-infiltrating lymphocytes (TILs), tumor-associated neutrophils (TANs), and CD3⁺ and CD79⁺ lymphocytes in canine mammary neoplasms with a solid arrangement, and associated such data with histological types, immunophenotype, prognostic factors, cyclooxygenase-2 (Cox-2) expression and overall and cancer-specific survival. Sixty-one neoplasms with a solid arrangement were classified as malignant myoepitheliomas (6/9.8%), solid papillary carcinomas (8/13.1%), carcinomas with a solid pattern (9/14.8%), basaloid carcinomas (BC) (19/31.1%), and malignant adenomyoepitheliomas (19/31.1%). Intra- and peritumoral TILs, TANs, and TCD3⁺ and BCD79⁺ lymphocytes were counted, and based on the resulting median, the neoplasms were divided into low or high cell infiltration. BCs had the lowest density of intratumoral TILs (p = 0.02), and luminal B neoplasms showed a significantly higher density of intratumoral TCD3⁺ than luminal A cases. Neoplasms with a higher density of peritumoral CD3⁺ and CD79⁺ had significantly greater proliferative activity. High infiltration of intratumoral BCD79⁺ lymphocytes was related to nodal metastasis (p = 0.03). Intratumoral TILs and TCD3⁺ were associated with shorter survival time. Therefore, intratumoral lymphocyte infiltration is possibly an important feature in the progression of cancer and influences the survival in bitches with solid arrangement neoplasms. Full article

Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment. Full article

One of the factors contributing to colorectal cancer (CRC) development is inflammation, which is mostly hypoxia-associated. This study aimed to characterize the morphological and molecular biological features of colon tumors in mice that were tolerant and susceptible to hypoxia based on colitis-associated CRC (CAC). Hypoxia tolerance was assessed through a gasping time evaluation in a decompression chamber. One month later, the animals were experimentally modeled for colitis-associated CRC by intraperitoneal azoxymethane administration and three dextran sulfate sodium consumption cycles. The incidence of tumor development in the distal colon in the susceptible to hypoxia mice was two times higher and all tumors (100%) were represented by adenocarcinomas, while in the tolerant mice, only 14% were adenocarcinomas and 86% were glandular intraepithelial neoplasia. The tumor area assessed on serially stepped sections was statistically significantly higher in the susceptible animals. The number of macrophages, CD3−CD19+, CD3+CD4+, and NK cells in tumors did not differ between animals; however, the number of CD3+CD8+ and vimentin+ cells was higher in the susceptible mice. Changes in the expression of genes regulating the response to hypoxia, inflammation, cell cycle, apoptosis, and epithelial barrier functioning in tumors and the peritumoral area depended on the initial mouse’s hypoxia tolerance, which should be taken into account for new CAC diagnostics and treatment approaches development. Full article

Similarly to our healthy organs, the tumor tissue also constitutes an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells and alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix; these processes promote epithelial–mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment; so, the successful inhibition of tumorous matrix remodeling could further enhance the success of antitumor therapy. Over the last decade, significant progress has been made with the introduction of novel immunotherapy that targets the inhibitory mechanisms of T cell activation. However, extensive research is also being conducted on the stromal components and other cell types of the tumor microenvironment (TME) that may serve as potential therapeutic targets. Full article

Colorectal cancer (CRC) is a significant public health problem. There is increasing evidence that the host’s immune response and nutritional status play a role in the development and progression of cancer. The aim of our study was to examine the prognostic value of clinical markers/indexes of inflammation, nutritional and pathohistological status in relation to overall survival and disease free-survival in CRC. The total number of CRC patients included in the study was 111 and they underwent laboratory analyses within a week before surgery. Detailed pathohistological analysis and laboratory parameters were part of the standard hospital pre-operative procedure. Medical data were collected from archived hospital data. Data on the exact date of death were obtained by inspecting the death registers for the territory of the Republic of Serbia. All parameters were analyzed in relation to the overall survival and survival period without disease relapse. The follow-up median was 42 (24−48) months. The patients with the III, IV and V degrees of the Clavien–Dindo classification had 2.609 (HR: 2.609; 95% CI: 1.437−4.737; p = 0.002) times higher risk of death. The modified Glasgow prognostic score (mGPS) 2 and higher lymph node ratio carried a 2.188 (HR: 2.188; 95% CI: 1.413−3.387; p < 0.001) and 6.862 (HR: 6.862; 95% CI: 1.635−28.808; p = 0.009) times higher risk of death in the postoperative period, respectively; the risk was 3.089 times higher (HR: 3.089; 95% CI: 1.447−6.593; p = 0.004) in patients with verified tumor deposits. The patients with tumor deposits had 1.888 (HR: 1.888; 95% CI: 1024−3481; p = 0.042) and 3.049 (HR: 3.049; 95% CI: 1.206−7.706; p = 0.018) times higher risk of disease recurrence, respectively. The emphasized peritumoral lymphocyte response reduced the risk of recurrence by 61% (HR: 0.391; 95% CI: 0.196−0.780; p = 0.005). Standard perioperative laboratory and pathohistological parameters, which do not present any additional cost for the health system, may provide information on the CRC patient outcome and lay the groundwork for a larger prospective examination. Full article

(1) Background: Ultrasound (US) elastography is an imaging technology that reveals tissue stiffness. This study aimed to investigate whether fibrotic focus (FF) affects elastographic findings in breast cancer, and to evaluate the clinical significance of US elastography and FF in breast cancer. (2) Methods: In this study, 151 patients with breast cancer who underwent surgery were included. Strain elastography was performed and an elasticity scoring system was used to assess the findings. The elasticity scores were classified as negative, equivocal, or positive. FF was evaluated in the surgical specimens. Medical records were reviewed for all patients. (3) Results: Elastographic findings were equivocal in 30 patients (19.9%) and positive in 121 patients (80.1%). FF was present in 68 patients (46.9%). There was no correlation between elastographic findings and FF. Older age, larger tumor size, lymph node metastasis, and higher tumor stage were associated with positive elastographic results. FF showed a positive correlation with age, postmenopausal status, tumor size, lymphovascular invasion, lymph node metastasis, tumor stage, and intratumoral and peritumoral inflammation. (4) Conclusions: Our study showed that positive elastographic results and FF were associated with poor prognostic factors for breast cancer. FF did not affect the elastographic findings of this study. Full article

The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC. Full article

Podoplanin is a sialomucin-like type I transmembrane receptor glycoprotein that is expressed specifically in lymphatic vessels, sebaceous glands, and hair follicles in normal skin. However, under pathological conditions podoplanin expression is upregulated in various cells, such as keratinocytes, fibroblasts, tumor cells, and inflammatory cells, and plays pivotal roles in different diseases. In psoriasis, podoplanin expression is induced in basal keratinocytes via the JAK-STAT pathway and contributes toward epidermal hyperproliferation. Podoplanin expression on keratinocytes can also promote IL-17 secretion from lymphocytes, promoting chronic inflammation. During wound healing, the podoplanin/CLEC-2 interaction between keratinocytes and platelets regulates re-epithelialization at the wound edge. In skin cancers, podoplanin expresses on tumor cells and promotes their migration and epithelial-mesenchymal transition, thereby accelerating invasion and metastasis. Podoplanin is also expressed in normal peritumoral cells, such as cancer-associated fibroblasts in melanoma and keratinocytes in extramammary Paget’s disease, which promote tumor progression and predict aggressive behavior and poor prognosis. This review provides an overview of our current understanding of the mechanisms via which podoplanin mediates these pathological skin conditions. Full article

Oral squamous cell carcinoma (OSCC) incidence has increased by 50% over the last decade. Unfortunately, surgery and adjuvant radiotherapy and chemotherapy are still the mainstream modality of treatment, underscoring the need for alternative therapies. Somatostatin-analogues (SSA) are efficacious and safe treatments for a variety of tumors, but the presence of somatostatin-receptors (SSTs) and pharmacological effects of SSA on OSCC are poorly known. In this study, we demonstrated that SST₂ and SST₃ levels were significantly higher in OSCC, compared to adjacent healthy control tissues. SST₂ expression was associated with less regional metastasis and a lower recurrence rate. Moreover, SST₂ was elevated in OSCC and associated with histopathological good prognosis factors, such as high peritumoral inflammation, smaller depth of invasion, and expansive vs. infiltrative front of tumor invasion. Importantly, treatment with different SSA (octreotide, lanreotide, and pasireotide) significantly reduced cell-proliferation in OSCC primary cell cultures. Altogether, this study demonstrated that SST₂ is overexpressed in OSCC vs. healthy tissues and could represent a novel prognostic biomarker, since its expression is associated with tumors that show better prognostic factors and less recurrent rate. Moreover, our data unveil clear antitumoral effects of SSAs on OSCC, opening new avenues to explore their potential as targeting therapy to OSCC. Full article