Folliculo-stellate cells (FSCs) constitute 5-10 % of the adenohypophysis and have been proposed as paracrine regulators of pituitary cells. However, their participation in pituitary tumor development remains unclear. We generated a lacto-somatotropic tumor model by subcutaneous injection of GH3 (lacto-somatotrophs) and the FSCs TtT/GF, isolated or combined, in immunodeficient mice, to study the role of the FSCs on tumor formation, hormone secretion, vascularization and extra-cellular matrix involvement. The co-culture of both cell lines let us gain insight into the proliferative and secretory action of FSC in pituitary tumor modulation. Our results showed that initially GH3:TtT/GF tumors had an earlier onset, but lately, TtT/GF cells restrained GH3:TtT/GF tumor growth and their Prl synthesis, although no differences were observed in the proliferative potential of tumor cells in vivo. Instead, TtT/GF cells exerted a direct mitogenic action on GH3 cells in vitro. Moreover, GH3 tumors had fewer irrigating vessels, lower vascular area and a higher VEGF/bFGF ratio that correlated with Hif1a expression, consistent with the tissue hypoxia and hemorrhage. These features were downregulated in their co-injected counterparts, which interestingly showed an increased deposition of collagens, glycoproteins and mucopolysaccharides extra-cellular matrix (EMC) components. Isolated TtT/GF injected cells did not generate tumors, but they developed fibrous masses characterized by collagen and high bFGF production. In conclusion, our results demonstrate that FSCs are dual regulators of pituitary tumor growth, with a mitogenic action on tumor cells but also a restrictive tumor effect on the cancer processes angiogenesis, hypoxia, and ECM remodeling.

Diffusion MRI models accounting for varying diffusion times and high b-values, such as VERDICT, hold potential for non-invasively characterizing tumor tissue types, potentially enabling improved tumor grading, and treatment evaluation. Furthermore, cluster analysis can aid in identifying multidimensional patterns in the diffusion MRI (dMRI) data that are not apparent when analyzing individual parameters in isolation. The aim of this study was to evaluate how well cluster analysis of VERDICT parameters can be used for intratumor tissue characterization compared to ADC in a mouse model of human small intestine neuroendocrine tumor (GOT1), and to validate the method by histological analysis. Mice implanted with GOT1 were irradiated and subsequently imaged using a dMRI protocol designed for estimation of VERDICT parameters and ADC values. Histological analysis using hematoxylin and eosin (H&E), Masson's trichrome, and Ki67 staining identified three distinct tumor tissue types: necrotic, fibrotic, and viable tumor tissue. ROIs were drawn on regions of high and low ADC, which spatially matched with necrosis or fibrosis, and viable tumor tissue, respectively. Among the VERDICT parameters, the cell radius index (R) was most effective in distinguishing between necrotic and fibrotic tissue, whereas the intracellular fraction (fIC) was the most effective in differentiating viable from non-viable tissue. A Gaussian mixture model (GMM) of three clusters, representing each tumor tissue type, was fitted to R and fIC of all tumor voxel data. VERDICT cluster maps corresponded well with the histology classification maps overall. Fibrotic tissue corresponded best with the cluster of low fIC and low R, necrotic tissue with the cluster of low fIC and high R, and viable tumor tissue with the cluster of high fIC and intermediate R. In conclusion, GMM cluster analysis of VERDICT MRI data shows potential in differentiating necrotic, fibrotic, and viable tumor tissue in irradiated GOT1 tumors.

Fluorescence image-guided surgery (FIGS) offers high spatial resolution and real-time feedback but is limited by shallow tissue penetration and autofluorescence from current clinically approved fluorophores. The near-infrared (NIR) spectrum, specifically the NIR-I (700-900 nm) and NIR-II (950-1700 nm), addresses these limitations with deeper tissue penetration and improved signal-to-noise ratios. However, biological barriers and suboptimal optical performance under surgical conditions have hindered the clinical translation of NIR-I/II nanoprobes. In vivo mouse models have shown promise, but these models do not replicate the complex optical scenarios encountered during real-world surgeries. Existing tissue-mimicking phantoms used to evaluate NIR-I/II imaging systems are useful but fall short when assessing nanoprobes in surgical environments. These phantoms often fail to replicate the tumor microenvironment, limiting their predictive assessment. To overcome these challenges, we propose developing tumor-mimicking phantom models (TMPs) that integrate key tumor features, such as tunable tumor cell densities, in vivo-like nanoparticle concentrations, biologically relevant factors (pH, enzymes), replicate light absorption components (hemoglobin), and light scattering components (intralipid). These TMPs enable more clinically relevant assessments of NIR-I/II nanoprobes, including optical tissue penetration profiling, tumor margin delineation, and ex vivo thoracic surgery on porcine lungs. The components of TMPs can be further modulated to closely match the optical profiles of in vivo and ex vivo tumors. Additionally, 3D bioprinting technology facilitates a high-throughput platform for screening nanoprobes under realistic conditions. This approach will identify high-performing NIR-I/II probes with superior surgical utility, bridging the gap between preclinical findings and clinical applications, and ensuring results extend beyond traditional in vivo mouse studies.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies.

This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo.

Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT).

Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC.

Stromal components of the tumour microenvironment, such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM), are actively involved in tumorigenesis. CAFs and the ECM co-evolve with resultant molecular and mechanical pressure on tumour cells mediated by CAFs via the ECM. Meanwhile, ECM fibers determine CAF differentiation and activity, establishing a protumorigenic feed-forward loop. Oesophageal cancer carries a high morbidity and mortality, and curative surgical resection is only an option for a limited number of patients while early lymphatic spread and poor therapeutic responses are common. Although studies report marked heterogeneity in investigation of the stromal density of gastrointestinal cancers, it is generally accepted that oesophageal cancer is highly fibrotic, and stromal components like CAFs may outnumber cancer cells. Therefore, a comprehensive understanding of the reciprocal interaction between CAFs and the ECM in oesophageal cancer is essential to improving diagnostics and prognostication, as well as designing innovative anti-cancer strategies. Here, we summarise current understanding of oesophageal cancer from a stromal perspective. Then, we discuss that CAFs and the ECM in oesophageal cancer can independently and synergistically contribute to tumour progression and therapeutic resistance. We also summarise potential stromal targets that have been described in transcriptomic analyses, highlighting those validated in downstream experimental studies. Importantly, clinical translation of stromal-targeting strategies in oesophageal cancer is still in its infancy but holds significant promise for future therapeutic combinations.

Recent studies have highlighted the potential of local anesthetics (LA) as adjuvants in cancer treatment, specifically by increasing survival rates when used in surgical excisions. However, the clinical use of LA is restricted due to their systemic toxicity. The development of drug delivery systems could address this issue and advance the utilization of these molecules. In this research, we explored the pharmacokinetics (using microdialysis probes) and antitumor properties of a nanostructured lipid carrier (NLC) formulation containing the commercially available enantiomeric excess form of bupivacaine (BVCS75). This NLC was prepared with lavender oil (NLC-L-BVC), an excipient with inherent antitumor properties. We compared this formulation to a control (NLC-BVC) using synthetic lipids. Pharmacokinetic assessments of the NLCs confirmed the sustained release of BVCS75 within the tumor, characterized by a reduced elimination rate constant and longer half-life (∼6×). The encapsulation of BVCS75 within nanoparticles (whether natural or synthetic) enhanced its effectiveness in treating the primary tumor, resulting in the inhibition of tumor growth (70% with NLC-L-BVC and 72% with NLC-BVC), outperforming free BVC (17% inhibition). However, the association of lavender oil with BVCS75 in an NLC did not yield synergistic properties. Furthermore, all BVCS75 treatments (whether free or encapsulated) improved animal survival rates. These findings confirm that encapsulation of bupivacaine in NLC can prolong drug action at the local site, contributing to improved local antitumor therapy while mitigating systemic effects.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) are key components of the immunosuppressive tumor microenvironment and represent significant obstacles to effective immunotherapy. Phyllanthus emblica L. (PE), a medicinal plant traditionally used in Tibet, has shown therapeutic promise. This study investigates the effects of the tannin fraction of PE (PE-TF) on HCC and its ability to modulate the tumor immunosuppressive microenvironment.

We evaluated the antitumor efficacy of PE-TF using H22 xenografts and Hepa1-6 orthotopic mouse models. Transcriptomic analysis was performed to identify molecular targets underlying PE-TF suppression of HCC growth. Additionally, UPLC-MS/MS analysis identified the prototypic and metabolic components of PE-TF present in serum, tumor tissues, and adjacent normal liver tissues in the orthotopic HCC model.

PE-TF significantly suppressed tumor growth in both subcutaneous and orthotopic HCC models and promoted reprogramming of TAMs toward an antitumor M1 phenotype in vivo. Furthermore, PE-TF counteracted the protumoral effects mediated by bone marrow-derived macrophages (BMDMs) exposed to Hepa1-6-derived conditioned medium (HCM). Although TBH promoted macrophage M2 polarization, the reactive oxygen species (ROS)-scavenging activity of PE-TF effectively inhibited this process. Modulation of the tumor microenvironment by PE-TF-enhanced CD8+T cell infiltration and bolstered their antitumor response, as evidenced by increased transcription of perforin, IFN-γ, and IL-2. Transcriptomic analysis further revealed that T-cell receptor and cytotoxic T-cell signaling pathways are critical mediators of PE-TF' therapeutic effects. Moreover, we preliminarily characterized 79 components across serum, liver, and tumor tissues, and identified metabolic pathways for PE-TF ingredients-including methylation and glycosylation modifications of tumor-enriched constituents. Notably, seven components, such as corilagin and urolithin D, are hypothesized to possess immunomodulatory properties.

Our findings underscore the potential of PE-TF as an adjuvant immunotherapy for HCC. By scavenging ROS, PE-TF reverses the immunosuppressive M2-TAM phenotype and remodels the tumor microenvironment, thereby enhancing antitumor immunity. Additionally, integrating chemical and metabolic profiling offers a promising strategy for refining candidate selection in future drug discovery endeavors.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inheritable disease of cystic degeneration in the kidney. ADPKD is a significant cause of end-stage renal disease (ESRD). Autosomal Dominant Polycystic Liver Disease (ADPLD) results in substantial PLD with minimal PKD. Currently, there are eight genes which have been associated with ADPKD (PKD1 and PKD2), ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B), or both (GANAB). The severity of ADPKD can show an extremely broad range, but the evolution to ESRD is doubtless unavoidable. In some patients, carcinogenesis develops with inflammation as a potential promoting factor. In this chapter, we illustrate the severity of ADPKD and the fate to develop renal cell carcinoma (RCC).

Soft-tissue fibroproliferative conditions (FPCs) affect many organs. All demonstrate the accumulation of (myo)fibroblasts and extracellular matrix. Currently, FPCs are classified according to the affected body site/organ. To promote research into the etiological mechanisms that drive pathological FPCs, we propose a new, more clinically grounded, FPC classification that is based on the intent and severity of the fibroproliferation. There are three categories: responsive, replacement, and reconstructive FPCs. Reconstructive FPCs (e.g., keloids) have quasi-neoplastic behaviors, including local invasiveness, and serve as a bridge between fibrosis and cancers. Comparisons of reconstructive FPCs to both cancers and the other FPC categories may help elucidate their pathogenic cellular properties, microenvironmental components, and intracellular-signaling mechanisms. Thus, the new FPC classification may promote research in the fibrosis field.

The prognostic value of Fibrosis-4 (FIB-4) index, concerning KRAS status (wild-type [wtKRAS] vs. mutated [mutKRAS]) remains unclear in post-hepatectomy colorectal liver metastases (CRLM). We evaluated the combined impact of FIB-4 and Tumor Burden Score (TBS) on overall survival (OS)/recurrence-free survival (RFS), stratified by KRAS status.

CRLM patients undergoing hepatectomy (2000-2020) were analyzed, grouped by TBS/FIB-4.

Among 828 patients, 196 had high FIB-4. High TBS had worse 5-year OS (P < 0.001). In wtKRAS, high TBS correlated with worse OS (P < 0.001), but not in mutKRAS. High FIB-4 correlated with worse OS (P = 0.01). Sub-stratification showed no OS difference by FIB-4 in wtKRAS, but a difference in mutKRAS (P = 0.03). Multivariable analysis identified mutKRAS (HR: 1.90), high TBS (HR: 1.62), and FIB-4 (HR: 1.15) as mortality risk factors. The TBS-FIB-4-KRAS index had highest predictive accuracy. For RFS, TBS and FIB-4 independently stratified outcomes. High TBS was associated with worse RFS in wtKRAS (P < 0.001) but not in mutKRAS. High FIB-4 decreased RFS in mutKRAS (P = 0.001) but not in wtKRAS. FIB-4 was associated with a 10% increased recurrence risk.

TBS and FIB-4, alongside KRAS status, should be considered to improve outcome predictions.

Quinolones and their analogues are a remarkable group of drugs that have multiple impacts on the human immune system. They are suspected to mediate anti-cancer and anti-inflammatory responses. However, due to their effectiveness in treating a number of significant diseases, such as genitourinary cancer and breast cancer, as well as their antiangiogenic and immunomodulatory qualities, interest in this group of traditional medicines has recently increased. Unfortunately, numerous side effects were observed, such as diarrhea, skin rashes, nausea, vomiting, bleeding, and abnormal liver functions. To overcome these restrictions and to enhance the pharmacological profile, research efforts are focusing on the synthesis and optimization of novel quinolone analogues that lack severe side effects. The present study focuses on the mechanism of action and the signaling pathway involving the 4-anilinoquinolinylchalcone derivative. The objective of the present work was to better understand the mechanism by which anti-fibrosis is mediated by screening 6 synthesized 4-anilinoquinolinylchalcone derivatives for their potential as novel anti-fibrosis therapeutics.

Fibroinflammation refers to the highly integrated fibrogenic and inflammatory responses mediated by the concerted function of fibroblasts and innate immune cells in response to tissue perturbation. This process underlies the desmoplastic remodelling of the tumour microenvironment and thus plays an important role in tumour initiation, growth and metastasis. More specifically, fibroinflammation alters the biochemical and biomechanical signalling in malignant cells to promote their proliferation and survival and further supports an immunosuppressive microenvironment by polarizing the immune status of tumours. Additionally, the presence of fibroinflammation is often associated with therapeutic resistance. As such, there is increasing interest in targeting this process to normalize the tumour microenvironment and thus enhance the treatment of solid tumours. Herein, we review advances made in unravelling the complexity of cancer-associated fibroinflammation that can inform the rational design of therapies targeting this.

Breast cancer is a heterogeneous disease with variable responses to neoadjuvant chemotherapy (NACT). Evaluating the histopathological and immune changes in post-NACT breast cancer specimens is crucial for understanding treatment response and guiding further management. This study aims to assess tumor burden using the Residual Cancer Burden (RCB) index, examine histological alterations, evaluate immune activity through tumor-infiltrating lymphocytes (TILs), and analyze proliferative capacity via Ki-67 expression in post-NACT breast cancer specimens. A cross-sectional study of 50 modified radical mastectomy (MRM) specimens post-NACT was conducted. The histopathological analysis included tumor regression changes, stromal and cellular alterations, and nodal involvement. Immune response was assessed by quantifying TILs, and proliferation was measured using the Ki-67 index. Statistical correlations were made between clinicopathological parameters, TILs, and Ki-67 expression. Residual disease was detected in 39 cases (78%), and 11 cases (22%) had no residual disease. Among the 39 cases with residual disease, the majority were classified as RCB II (22 cases, 56%), 16 cases (41%) were classified as RCB III, and one case (3%) was classified as RCB I. Common histological changes post-NACT included fibrosis in 31 cases (62%), necrosis in 19 cases (38%), and infiltration by foamy histiocytes in 16 cases (32%). Malignant epithelial cells more frequently exhibited foamy cytoplasm (16 cases (41%) vs. two cases (5%); p=0.0003), hyperchromatic nucleus (26 cases (67%) vs. six cases (15%); p=0.0001), and prominent nucleoli (26 cases (67%) vs. four cases (10%); p=0.0001) compared to benign cells. Among the 39 cases with residual disease, low TIL and high Ki-67 expression were observed in 20 cases (51%), while 12 cases (32%) showed high TIL and low Ki-67. Residual tumors with high TIL and high Ki-67 (four cases, 10%) and low TIL and low Ki-67 (three cases, 8%) were less common. A significant inverse relationship was found between TIL levels and Ki-67 expression (p=0.0002), as tumors with low TIL were more likely to have high Ki-67 expression (20 cases, 51%), whereas those with high TIL more frequently exhibited low Ki-67 expression (12 cases, 32%). Post-NACT evaluation of tumor burden, immune landscape, and proliferation provides valuable prognostic insights. Integrating RCB, TILs, and Ki-67 into routine pathological assessment may aid patient stratification and guide personalized treatment strategies. Further large-scale studies are needed to validate these findings and improve therapeutic decision-making in breast cancer management.

In contemporary times, cancer poses the most significant threat to human life and safety. Scientists have relentlessly pursued the intricacies of carcinogenesis and explored ways to prevent and treat cancer. Carcinogenesis is a complex, multi-faceted, and multi-stage process, with numerous underlying causes, including inflammation and fibrosis. Cancer-associated fibroblasts (CAFs), however, occupy a pivotal and substantial role within the tumor microenvironment, facilitating carcinogenesis through diverse mechanisms such as creating inflammation, fostering a fibrotic tumor microenvironment, and immunosuppression. In this paper, we introduce the concept of carcinogenesis, explain its causes, describe the characteristics of CAFs and their sources, and highlight the roles and mechanisms of CAFs in promoting carcinogenesis. Ultimately, our aim is to contribute to the development of novel therapeutic strategies for cancer treatment.

The importance of collagen and elastin remains incompletely understood concerning tumor immunity in cancer tissues. This study explored the clinical significance of collagen and elastin deposition on tumor immunity in advanced colorectal cancer patients. The collagen and elastin contents were assessed simultaneously using elastic van Gieson (EVG) histochemical staining. Immunohistochemical staining was performed to measure the immune cell markers CD3, CD8, CD86, and CD163 in surgically resected primary tumors from 78 pT4 colorectal cancer patients. High collagen, elastin, and EVG scores are associated with aggressive characteristics and short disease-free survival. A high EVG score was identified as an independent predictor of poor disease-free survival. Furthermore, tumors with high collagen and EVG scores exhibited significantly fewer intratumoral CD3 + and CD8 + cells. Evaluating tumor fibrosis using the classical and straightforward EVG staining method could be a reliable predictor of recurrence in high-risk colorectal cancer patients with tumor immune tolerance.

Despite the great success that chimeric antigen receptor (CAR) T-cells have had in patients with B-cell malignancies and multiple myeloma, they continue to have limited efficacy against most solid tumors. Especially in the pediatric population, pre- and post-treatment biopsies are rarely performed due to ethical reasons, and thus, our understanding is still very limited regarding the mechanisms in the tumor microenvironment by which tumor cells exclude effectors and attract immune-suppressive cells. Nevertheless, based on the principles that are known, current T-cell engineering has leveraged some of these processes and created more potent CAR T-cells. The recent discovery of new oncofetal antigens and progress made in CAR design have expanded the potential pool of candidate antigens for therapeutic development. The most promising approaches to enhance CAR T-cells are novel CAR gating strategies, creative ways of cytokine delivery to the TME without enhancing systemic toxicity, and hijacking the chemokine axis of tumors for migratory purposes. With these new modifications, the next step in the era of CAR T-cell development will be the clinical validation of these promising preclinical findings.

Peritumoral fibrosis is known to promote cancer progression and confer treatment resistance in various solid tumors. Consequently, developing accurate cancer research and drug screening models that replicate the structure and function of a fibrosis-surrounded tumor mass is imperative. Previous studies have shown that self-assembly three-dimensional (3D) co-cultures primarily produce cancer-encapsulated fibrosis or maintain a fibrosis-encapsulated tumor mass for a short period, which is inadequate to replicate the function of fibrosis, particularly as a physical barrier. To address this limitation, a multi-layer spheroid formation method is developed to create a fibrosis-encapsulated tumoroid (FET) structure that maintains structural stability for up to 14 days. FETs exhibited faster tumor growth, higher expression of immunosuppressive cytokines, and equal or greater resistance to anticancer drugs compared to their parental tumoroids. Additionally, FETs serve as a versatile model for traditional cancer research, enabling the study of exosomal miRNA and gene functions, as well as for mechanobiology research when combined with alginate hydrogel. Our findings suggest that the FET represents an advanced model that more accurately mimics solid cancer tissue with peritumoral fibrosis. It may show potential superiority over self-assembly-based 3D co-cultures for cancer research and drug screening, and holds promise for personalized drug selection in cancer treatment.

The prognostic role of the fibrosis-4 (FIB-4) index relative to intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study sought to characterize the impact of the FIB-4 index and tumor burden score (TBS) on recurrence and overall survival (OS).

ICC patients undergoing hepatectomy (2000-2020) were identified using a multi-institutional database. Patients were categorized as low (low TBS/low FIB-4 index), intermediate (low TBS/high FIB-4 index or high TBS/low FIB-4 index), and high (high TBS/high FIB-4 index).

Among 1168 patients in different TBS and FIB-4 index cohorts, 3-year recurrence varied considerably. For instance, among the patients with low TBS, individuals with a high FIB-4 index had a greater risk of recurrence than patients with a low FIB-4 index (59.9 vs. 47.7%; P = 0.01). Among patients with a high TBS, individuals with a high versus a low FIB-4 index had a higher incidence of recurrence (76.8 vs. 69.0%; P = 0.04). A similar pattern was observed among patients with both a low FIB-4 index (low [47.7%] vs. high [69.0%] TBS) and a high FIB-4 index (low [59.9%] vs. high [76.8%] TBS; both P < 0.001). Patients with a high [27.5%] versus a low [48.8%] TBS; P < 0.001) and patients with a high [34.2%] versus a low [43.5%] FIB-4 index; P = 0.01) had a worse OS. The multivariable analysis demonstrated an increasing risk of recurrence in the intermediate-index (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.20-2.16; P = 0.001) and high-index (HR, 2.13; 95% CI 1.45-3.13; P < 0.001) groups versus the low-index group.

Both tumor-related and non-tumorous characteristics should be used to predict risk of recurrence and survival more accurately among patients with ICC following hepatic resection.

Abnormal lipid metabolism plays an important role in cancer development. In this study, nontargeted lipidomic study on 230 tissue specimens from 79 nonsmall cell lung cancer (NSCLC) patients was conducted using ultraperformance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Downregulation of sphingosine and medium-long-chain ceramides and short-medium-chain acylcarnitine, upregulation of long-chain acylcarnitine C20:0, and enhanced histamine methylation were revealed in NSCLC tissues. Compared with paired noncancerous tissues, adenocarcinoma (AC) tissues had significantly decreased levels of sphingosine, medium-long-chain ceramides (Cer d18:1/12:0 and Cer d16:1/14:0, Cer d18:0/16:0, Cer d18:1/16:0, Cer d18:2/16:0, Cer d18:2/18:0), short-medium-chain (C2-C16) acylcarnitines, LPC 20:0 and LPC 22:1, and significantly increased levels of the long-chain acylcarnitine C20:0, LPC 16:0, LPC P-16:0, LPC 20:1, LPC 20:2, glyceroPC, LPE 16:0, and LPE 18:2. In squamous cell carcinoma (SCC) tissues, sphingosine, Cer d18:2/16:0 and Cer d18:2/18:0, and short-medium-chain acylcarnitines had significantly lower levels, while long-chain acylcarnitines (C20:0, and C22:0 or C22:0 M), LPC 20:1, LPC 20:2, and N1,N12-diacetylspermine had significantly higher levels compared to controls. In AC and SCC tissues, the levels of LPG 18:0, LPG 18:1, and LPS 18:1 were significantly decreased, while the levels of ceramide-1-phosphate (C1P) d18:0/3:0 or LPE P-16:0, N1-acetylspermidine, and 1-methylhistamine were significantly increased than controls. Furthermore, an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model based on a 4-lipid panel was established, showing good discrimination ability between cancerous and noncancerous tissues.

Current research on tumor fibrosis has focused on cancer-associated fibroblasts, which may exert dual functions of tumor promotion and inhibition. Little attention has been paid to whether tumor cells themselves can undergo fibrotic transformation and whether they can inhibit parenchymal cells similar to pulmonary fibrosis, thus achieving the goal of inhibiting the malignant progression of tumors. To explore the significance of inducing tumor fibrosis for cancer treatment. This study utilizes mesoporous silica nanoparticles (MSN) loaded with Trehalose dimycolate (TDM) to induce tumor cell fibrosis through the dual effects of TDM-induced inflammatory granuloma and MSN-induced foreign body granuloma. The results show that TDM/MSN (TM) can effectively induce tumor fibrosis, manifested specifically by collagen internalization, and suppression of proliferation and invasion capabilities, suggesting the potential role of tumor fibrosis therapy. However, further investigation reveals that extrachromosomal DNA (ecDNA) mediates resistance to fibrosis induction. To comprehensively enhance the efficacy, WRN exonuclease is conjugated to TM to form new nanoparticles (TMW) capable of effectively eliminating ecDNA, globally promoting tumor cell fibroblast-like transformation, and validated in a PDX model to inhibit cancer progression. Therefore, TMW, through inducing tumor cell fibrosis to inhibit its malignant progression, holds great potential as a clinical treatment strategy.

Dendritic cells (DCs) are antigen-presenting cells that reside in peripheral tissues and are responsible for initiating adaptive immune responses. As gatekeepers of the immune system, DCs need to continuously explore their surroundings, for which they can rapidly move through various types of connective tissue and basement membranes. DC motility has been extensively studied on flat 2D surfaces, yet the influences of a contextual 3D fibrous environment still need to be described. Using ECM-mimicking suspended fiber networks, we show how immature DCs (iDCs) engage in migratory cycles that allow them to transition from persistent migration to slow migratory states. For a subset of iDCs with high migratory potential, we report the organization of protrusions at the front of the cell body, which reverses upon treatment with inflammation agent PGE2. We identify an unusual migratory response to aligned fiber networks, whereby iDCs use filamentous protrusions to attach laterally and exert forces on fibers to migrate independent of fiber alignment. Increasing the fiber diameter from 200 to 500 nm does not significantly affect the migratory response; however, iDCs respond by forming denser actin bundles around larger diameters. Overall, the correlation between force-coupling and random migration of iDCs in aligned fibrous topography offers new insights into how iDCs might move in fibrous environments in vivo.

The prevalence of end-stage renal disease is increasing worldwide. Malignancies accompanying end-stage renal disease are detected in approximately 120 individuals per 10,000 person-years. Most studies have suggested that end-stage renal disease causes carcinogenesis and promotes tumor development; however, this theory remains questionable. Contrary to the theory that end-stage renal disease is predominantly carcinogenic, recent findings have suggested that after controlling for biases and sampling errors, the overall cancer risk in patients with end-stage renal disease might be lower than that in the general population, except for renal and urothelial cancer risks. Additionally, mortality rates associated with most cancers are lower in patients with end-stage renal disease than in the general population. Several biological mechanisms have been proposed to explain the anticancer effects of end-stage renal disease, including premature aging and senescence, enhanced cancer immunity, uremic tumoricidal effects, hormonal and metabolic changes, and dialysis therapy-related factors. Despite common beliefs that end-stage renal disease exacerbates cancer risk, emerging evidence suggests potential tumor-suppressive effects. This review highlights the potential anticancer effects of end-stage renal disease, proposing reconsideration of the hypothesis that end-stage renal disease promotes cancer development and progression.

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

Prostate cancer (PC) is an age-related disease and represents, after lung cancer, the second cause of cancer death in males worldwide. Mortality is due to the metastatic disease, which mainly involves the bones, lungs, and liver. In the last 20 years, the incidence of metastatic PC has increased in Western Countries, and a further increase is expected in the near future, due to the population ageing. Current treatment options, including state of the art cancer immunotherapy, need to be more effective to achieve long-term disease control. The most significant anatomical barrier to overcome to improve the effectiveness of current and newly designed drug strategies consists of the prostatic stroma, in particular the fibroblasts and the extracellular matrix, which are the most abundant components of both the normal and tumor prostatic microenvironment. By weaving a complex communication network with the glandular epithelium, the immune cells, the microbiota, the endothelium, and the nerves, in the healthy prostatic microenvironment, the fibroblasts and the extracellular matrix support organ development and homeostasis. However, during inflammation, ageing and prostate tumorigenesis, they undergo dramatic phenotypic and genotypic changes, which impact on tumor growth and progression and on the development of therapy resistance. Here, we focus on the characteristics and functions of the prostate associated fibroblasts and of the extracellular matrix in health and cancer. We emphasize their roles in shaping tumor behavior and the feasibility of manipulating and/or targeting these stromal components to overcome the limitations of current treatments and to improve precision medicine's chances of success.

Label-free multimodal imaging methods that can provide complementary structural and chemical information from the same sample are critical for comprehensive tissue analyses. These methods are specifically needed to study the complex tumor-microenvironment where fibrillar collagen's architectural changes are associated with cancer progression. To address this need, we present a multimodal computational imaging method where mid-infrared spectral imaging (MIRSI) is employed with second harmonic generation (SHG) microscopy to identify fibrillar collagen in biological tissues.

To demonstrate a multimodal approach where a morphology-specific contrast mechanism guides an MIRSI method to detect fibrillar collagen based on its chemical signatures.

We trained a supervised machine learning (ML) model using SHG images as ground truth collagen labels to classify fibrillar collagen in biological tissues based on their mid-infrared hyperspectral images. Five human pancreatic tissue samples (sizes are in the order of millimeters) were imaged by both MIRSI and SHG microscopes. In total, 2.8 million MIRSI spectra were used to train a random forest (RF) model. The other 68 million spectra were used to validate the collagen images generated by the RF-MIRSI model in terms of collagen segmentation, orientation, and alignment.

Compared with the SHG ground truth, the generated RF-MIRSI collagen images achieved a high average boundary F -score (0.8 at 4-pixel thresholds) in the collagen distribution, high correlation (Pearson's R 0.82) in the collagen orientation, and similarly high correlation (Pearson's R 0.66) in the collagen alignment.

We showed the potential of ML-aided label-free mid-infrared hyperspectral imaging for collagen fiber and tumor microenvironment analysis in tumor pathology samples.

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms.

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Chronic hepatitis C virus (HCV) infection is a major cause of hepatic fibrosis and cirrhosis, with a risk for the development of hepatocellular carcinoma (HCC). Although highly effective direct-acting antivirals (DAAs) are available, the incidence, morbidity, and mortality of HCV-associated HCC are still high. This article reviews the current knowledge of the mechanisms of HCV-induced carcinogenesis with a special focus on those processes that continue after virus clearance and outlines implications for patient surveillance after DAA treatment.

Fibrosis, which is primarily marked by excessive extracellular matrix (ECM) deposition, is a pathophysiological process associated with many disorders, which ultimately leads to organ dysfunction and poor patient outcomes. Despite the high prevalence of fibrosis, currently there exist few therapeutic options, and importantly, there is a paucity of in vitro models to accurately study fibrosis. This review discusses the multifaceted nature of fibrosis from the viewpoint of developing organ-on-chip (OoC) disease models, focusing on five key features: the ECM component, inflammation, mechanical cues, hypoxia, and vascularization. The potential of OoC technology is explored for better modeling these features in the context of studying fibrotic diseases and the interplay between various key features is emphasized. This paper reviews how organ-specific fibrotic diseases are modeled in OoC platforms, which elements are included in these existing models, and the avenues for novel research directions are highlighted. Finally, this review concludes with a perspective on how to address the current gap with respect to the inclusion of multiple features to yield more sophisticated and relevant models of fibrotic diseases in an OoC format.

CD45 plays a crucial role in the regulation of hematopoiesis. However, a comprehensive understanding of its role in non-hematopoietic cells is lacking. Several tissue precursors express CD45, indicating its crucial role in tissue regeneration. These precursors would fall prey to the recent therapies involving CD45 as a target. CD45+ double-positive tumor cells contribute to cancer progression, but whether CD45 is involved in the process needs to be investigated. Recently, we showed that aging induces CD45 expression in mesenchymal stromal cells and affects their differentiation potential. In this review, we, for the first time, unravel the important implications of the expression of CD45 in non-hematopoietic cells and provide novel insights into its potential therapeutic target in regenerative medicine and disease management.

Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.

Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.

Sustained injury from factors such as hypoxia, infection, or physical damage may provoke improper tissue repair and the anomalous deposition of connective tissue that causes fibrosis. This phenomenon may take place in any organ, ultimately leading to their dysfunction and eventual failure. Tissue fibrosis has also been found to be central in both the process of carcinogenesis and cancer progression. Thus, its prompt diagnosis and regular monitoring is necessary for implementing effective disease-modifying interventions aiming to reduce mortality and improve overall quality of life. While significant research has been conducted on these subjects, a comprehensive understanding of how their relationship manifests through modern imaging techniques remains to be established. This work intends to provide a comprehensive overview of imaging technologies relevant to the detection of fibrosis affecting thoracic organs as well as to explore potential future advancements in this field.

The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.