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PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗
PubMed2025

Microbial signals in primary and metastatic brain tumors.

Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases samples, localized to tumor, immune and stromal cells. Custom 16S and metagenomic sequencing workflows identified taxa associated with intratumoral bacterial signals in the tumor microenvironment; however, standard culture methods did not yield readily cultivable microbiota. Spatial analyses revealed significant correlations between bacterial 16S signals and antimicrobial and immunometabolic signatures at regional, neighborhood and cellular levels. Furthermore, intratumoral 16S bacterial signals showed sequence overlap with matched oral and gut microbiota, suggesting a possible connection with distant communities. Together, these findings introduce microbial elements as a component of the brain tumor microenvironment and lay the foundation for future mechanistic and translational studies.

Humans↗
PubMed2026

The IL-1 system in inflammation and cancer.

Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.

Humans↗
PubMedDate not supplied

Cancer invasion: watch your neighbourhood!

The critical event in neoplastic diseases is the invasion of surrounding tissue by cancer cells. This event greatly reduces treatment options, and makes cancer a lethal disease. Factors that initiate cancer invasion are not well understood, neither do we have mechanistic insights in the process itself. Recently, a new concept has emerged: the tissue surrounding tumor cells, ie, the tumor microenvironment, may play an important, if not decisive role in triggering invasion. This concept is based on data from many laboratories working on the cell biology of cancer invasion. In this review, we survey several components of the tumor microenvironment, including extracellular matrix macromolecules, metalloproteinases and soluble factors, and discuss their potential involvement in stimulating cancer cell motility. These novel views may have far-reaching consequences, since "normal" tissue microenvironment components, rather than the traditional tumor cells themselves, may eventually become targets for devising new treatments that prevent, inhibit or block cancer invasion and metastasis.

Extracellular Matrix Proteins↗
PubMed2002

Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway.

To examine whether the tumor microenvironment alters cytokine-induced cytotoxicity, human prostate adenocarcinoma DU-145 cells were exposed to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or glucose deprivation, a common characteristic of the tumor microenvironment. TRAIL alone reduced cell survival in a dose-dependent manner. Glucose deprivation alone induced no cytotoxicity within 4 h. However, the combination of TRAIL (50 ng/ml) and glucose deprivation for 4 h increased cell death and PARP cleavage by promoting activation of caspase-8 and caspase-3, relative to that of TRAIL alone. Similar results were observed in human colorectal carcinoma CX-1 cells. Data from immunoblotting analysis reveal that glucose deprivation-enhanced TRAIL cytotoxicity is inversely related to the intracellular level of FLICE inhibitory protein (FLIP) but not that of death receptor 5 (DR5). Results from mass spectrometry show that glucose deprivation elevates ceramide. The elevation of ceramide may cause dephosphorylation of Akt and maintain dephosphorylation of Akt in the presence of TRAIL and then subsequently down-regulate the expression of FLIP. Taken together, the present studies suggest that glucose deprivation enhances TRAIL-induced cytotoxicity through the ceramide-Akt-FLIP pathway.

Adenocarcinoma↗
PubMed2021

Deep generative neural network for accurate drug response imputation.

Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.

Antineoplastic Agents↗
PubMed2005

HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.

To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases (Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor-mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient (SCID) mice, the growth of these tumors was dramatically reduced on the order of 5- to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. (i) HSulf-1 and HSulf-2 have similar functions in vivo. (ii) The extracellular activity of Sulfs is restricted to the local tumor cell surface. (iii) The Sulfs promote a marked increase in extracellular matrix deposition within tumors that may, along with attenuated growth factor signaling, contribute to the reduction in tumor growth. These findings demonstrate that dynamic regulation of heparan sulfate structure by Sulfs present within the tumor microenvironment can have a dramatic impact on the growth and progression of malignant cells in vivo.

Animals↗
PubMed1986

Antitumor action of crotalase, a defibrinogenating snake venom enzyme.

Recent reports have shown that malignant cells release a variety of factors that modulate the tumor microenvironment. These factors, after release or shedding, work in concert to produce extravasation of fibrinogen from surrounding blood vessels with subsequent fibrin deposition around the tumor cells. This fibrin deposit could act to mask the tumor from the host's immune surveillance system. Fibrin deposits have been observed by investigators in the vicinity of various malignant tumors of man and animals. Although these observations suggest a role for the blood coagulation mechanism in tumor biology, the pathogenesis and significance of fibrin deposits in tumors have not been thoroughly investigated. We have used crotalase, a highly purified defibrinogenating serine proteinase from eastern diamondback rattlesnake venom and a fibrinolytic enzyme from southern copperhead venom to modulate selectively the tumor microenvironment in order to evaluate the role of fibrin(ogen) in tumor growth and dissemination. B16 melanoma, carried in C57BL/6 mice, has been selected as the experimental model system to evaluate the effectiveness of treatment by the venom enzymes. For these studies, solid B16 melanoma was excised from mice and a cell suspension was prepared in serum-free RPMI 1640 medium. Treatment of the cells with crotalase (30 NIH clotting U/ml) produced a dramatic inhibition of growth after subcutaneous injection of cells into C57BL/6 mice. On day 17 after implantation of tumor cells alone, the average tumor weight was 70 mg/mouse. By contrast, mice that received the B16 melanoma cells pretreated with crotalase had an average tumor mass of only 2 mg/mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2026

Intratumoral collagen correlates with histological grade and patient prognosis in breast cancer.

Histological grading, using the Nottingham Grading System (NGS), is a major prognostic indicator for breast cancer. NGS involves the scoring of cancer cell-related morphological features, yet it overlooks tumor microenvironment (TME) components such as collagen. Collagen proteins, integral to the extracellular matrix (ECM), influence tumor architecture and progression but their relationship with histological grade is not fully characterized. Here, we assessed intratumoral collagen deposition using Masson Trichrome staining of whole slides (n = 166), proteomic profiling (n = 2) and transcriptomic analyses of the METABRIC (n = 1827) and TCGA-BRCA (n = 753) cohorts. We showed that low-grade tumors display significantly higher intratumoral collagen deposition compared to high-grade tumors. Moreover, we demonstrated that collagen expression at the transcript and protein levels (Masson Trichrome) could discriminate Grade II carcinomas into distinct prognostic groups, in which patients with Grade II carcinomas with elevated levels of collagen expression were associated with lower pTNM stage and better survival outcomes. Our results support the inclusion of TME features, such as collagen deposition, to enhance prognostic accuracy in breast cancer.

Humans↗
PubMed1998

Immunocytokines: a promising approach to cancer immunotherapy.

Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8+ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.

Animals↗
PubMed2004

In vivo determination of tumor oxygenation during growth and in response to carbogen breathing using 15C5-loaded alginate capsules as fluorine-19 magnetic resonance imaging oxygen sensors.

PURPOSE: The objective was to present a method for the repeated noninvasive measurement of tumor oxygenation (Po(2)) over the whole period of tumor growth. METHODS AND MATERIALS: A mixture of tumor homogenate (GH3 prolactinoma) and alginate capsules loaded with perfluoro-15-crown-5-ether (15C5) was injected into the flanks of Wistar Furth rats. The temporal behavior of tumor Po(2) was monitored between Day 1 and 26 after injection using fluorine-19 ((19)F) magnetic resonance imaging (MRI). In addition, the response of tumor Po(2) to modifiers of the tumor microenvironment (carbogen [95% O(2)/5% CO(2)], nicotinamide, and hydralazine) was investigated. RESULTS: An initial increase of tumor Po(2), probably reflecting neovascularization, followed by a decrease after Week 2, probably indicating tumor hypoxia or necrosis, were observed. The minimum and maximum average Po(2) +/- SEM observed were 3.3 +/- 2.0 mm Hg on Day 2 and 25.7 +/- 3.8 mm Hg on Day 13, respectively. Carbogen increased the tumor Po(2), whereas nicotinamide caused no significant change and hydralazine induced a significant decrease in tumor oxygenation. CONCLUSIONS: A preclinical method for the repeated noninvasive determination of tumor Po(2) was presented. It might help to investigate tumor physiology and the mechanisms of modifiers of the tumor microenvironment and their role in different therapeutic approaches.

Alginates↗
PubMed2006

Chronic inflammation and pathogenesis of GI and pancreatic cancers.

The pathogenesis of cancer represents a complex and multifactorial process requiring a number of acquired and genetic defects. It is becoming increasingly apparent that many cancers originate from a chronic inflammatory process. The topic of this review is the inflammatory response and development of gastrointestinal (GI) and pancreatic cancers. Here, we describe the development of various gastric colorectal and pancreatic cancers through an inflammatory process. The tumor microenvironment which predisposes to tissue destruction, subsequent attempts at healing and accumulation of cellular damage with loss of cell cycle control mechanisms is discussed. Components of the tumor microenvironment that are important in the final common pathway leading to cancer include the tumor stroma, tumor-associated macrophages, cytokines and chemokines and reactive oxygen and nitrogen species. Common signaling pathways that link inflammation with cancer are described and include the COX-2, NF-kappaB and phosphatidyl inositol 3-kinase (PI3K) pathways. Finally, therapies that can be directed to the inflammatory process as either treatment or prevention of these cancers will be discussed including novel inhibitors of signaling pathways which are currently in development.

Anti-Inflammatory Agents↗
PubMed2006

Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression.

In the 1980's, as the importance of matrix metalloproteinases (MMPs) in cancer progression was discovered, it was recognized that in most tumors these proteases were abundantly and sometimes exclusively expressed not by tumor cells, but by normal host-derived cells like fibroblasts, vascular endothelial cells, myofibroblasts, pericytes or inflammatory cells that contribute to the tumor microenvironment. Later experiments in mice deficient in specific MMPs revealed that host-derived MMPs play a critical role not only in tumor cell invasion, but also in carcinogenesis, angiogenesis, vasculogenesis and metastasis. Tumor cells secrete many factors, cytokines and chemokines that directly or indirectly increase the expression of these MMPs in the tumor microenvironment where they exert extracellular matrix (ECM) degrading and sheddase activities. The knowledge of the complex role that stromal-derived MMPs play in the interaction between tumor cells and stromal cells should allow us to consider specific windows in cancer treatment when MMP inhibition could have a valuable therapeutic effect.

Animals↗
PubMed2006

B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.

Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.

Animals↗
PubMed1997

Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element.

Tumor angiogenesis, the development of new blood vessels, is a highly regulated process that is controlled genetically by alterations in oncogene and tumor suppressor gene expression and physiologically by the tumor microenvironment. Previous studies indicate that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF). In this report, we show Ras-transformed cells do not use the downstream effectors c-Raf-1 or mitogen activated protein kinases (MAPK) in signaling VEGF induction by hypoxia as overexpression of kinase-defective alleles of these genes does not inhibit VEGF induction under low oxygen conditions. In contrast to the c-Raf-1/MAP kinase pathway, hypoxia increases phosphatidylinositol 3-kinase (PI 3-kinase) activity in a Ras-dependent manner, and inhibition of PI 3-kinase activity genetically and pharmacologically results in inhibition of VEGF induction. We propose that hypoxia modulates VEGF induction in Ras-transformed cells through the activation of a stress inducible PI 3-kinase/Akt pathway and the hypoxia inducible factor-1 (HIF-1) transcriptional response element.

3T3 Cells↗
PubMed1997

[Microsensor-controlled feedback bioactuators as a semi-integrated basis for biophysical cancer treatment].

Acidic microenvironmental conditions combined with large hypoxic areas are ubiquitous hallmarks of most solid tumors. They result from a poorly organized vascularization and a deviant energy metabolism. There is convincing evidence supporting the hypothesis that such physico-chemical conditions promote the microevolution of malignant cells, inhibit the cellular immune response, and favor tumor cell invasion. In agreement with published data, our cell biological analyses and computer simulations indicate that treatment schemes which restore a tumor microenvironment reflecting that one found in normal tissues might improve the efficiency of immunotherapies and classical methods for cancer treatment. We suggest that the tumor microenvironment could be effectively monitored and manipulated by means of silicon-based feedback bioactuators which are controlled by integrated microsensors. In principle, miniaturized bioactuators can be implanted directly at the sites of inoperable tumors and metastases where they function as a "pH clamp" and thereby can reconstitute normal physicochemical conditions. Drug application could be precisely controlled by an integrated microprocessor. Our paper summarizes the current state of development of microsensor-based feedback bioactuators and outlines possible applications in biophysical cancer treatment.

Automation↗
PubMed2005

Growth of V79 cells as xenograft tumors promotes multicellular resistance but does not increase spontaneous or radiation-induced mutant frequency.

A Chinese hamster V79 xenograft model was developed to determine whether cells subjected to a hypoxic tumor microenvironment would be more likely to undergo mutation at the HPRT locus. V79-171b cells stably transfected with VEGF and EGFP were grown subcutaneously in immunodeficient NOD/ SCID mice. V79-VE tumors were characterized for host cell infiltration, doubling time, hypoxic fraction, vascular perfusion, and response to ionizing radiation. When irradiated in vitro, the mutant frequency for a given surviving fraction did not differ for cells grown in vivo or in vitro. Similar results were obtained using HCT116 human colorectal carcinoma cells grown as xenografts. However, V79-VE cells grown as xenografts were significantly more resistant to killing than monolayers. The background mutant frequency and the radiation-induced mutant frequency did not differ for tumor cells close to or distant from blood vessels. Similarly, tumor cells from well-perfused regions showed the same rate of strand break rejoining and the same rate of loss of phosphorylated histone H2AX as cells sorted from poorly perfused regions. Therefore, deleterious effects of the tumor microenvironment on DNA repair efficiency or mutation induction could not be demonstrated in these tumors. Rather, development of multicellular resistance in V79-VE tumors acted to reduce mutant frequency for a given dose of radiation.

Animals↗
PubMed2026

Tumor-associated macrophages display differential protein cargo sorting in extracellular vesicles associated with poor survival in ovarian cancer.

Ovarian cancer (OC) progression and metastasis are promoted by ascites, which constitutes a central part of the tumor microenvironment (TME). In this fluid, tumor-associated macrophages (TAMs) represent a prominent immune cell type. In addition to tumor and other host cells such as TAMs, ascites is highly enriched in soluble factors as well as extracellular vesicles (EVs). How TAMs contribute to the EV compartment of the OC TME remains, however, underexplored. In this work peripheral blood monocytes from healthy donors were differentiated into monocyte-derived macrophages (MDMs) and polarized into classically activated (M1-like), alternatively activated (M2-like) and TAM-like (by ascites incubation). For all subtypes, serum-free conditioned medium was collected for 24 h and EVs were isolated and characterized by nano-flow cytometry (nFC), label-free mass spectrometry-based proteomics and electron microscopy, among others. Our results demonstrated distinct traits for EV release and cargo across the different macrophage subtypes. Specifically, TAM-like macrophages exhibited impaired release of small EVs and reduced frequency of tetraspanin-positive particles. These EV subpopulations displayed sizing profiles closer to M1-like than to M2-like samples. Also, the low EV release in TAM-like MDMs was accompanied by altered expression of biogenesis-related markers like flotillin-1 (FLOT1) and a decreased N-glycosylation of CD63 protein, which was validated in patient-derived samples. Remarkably, the EV-associated proteome of TAMs displayed significant enrichment in both pro- and anti-inflammatory molecules with clinical value. Markers significantly enriched in the ascites TAM-EV signature were mostly associated with poor prognosis, whereas M1-like EV-related markers (pro-inflammatory) were mostly associated with longer survival. Our results confirmed previous data for proteins like CD163 and MRC1 to be associated to TAM-EVs, while also describing novel candidates with diagnostic (i.e., COLEC12) and/or prognostic (i.e., MSR1) value in plasma. Taken together, our data support a unique secretory profile of TAMs in OC and provide new EV-associated biomarkers with translational impact. Our results pave the way for a better understanding of the mechanisms behind TAM-EV cargo loading and function, and how these cells participate in the TME landscape.

Humans↗