The Tumor Microenvironment--Its Characterization, Modification and Clinical Implications. Proceedings of an international workshop. Granada, Spain, September 23-25, 1994.
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Animals↗
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Tumor microenvironment and immune effector cells. Introduction.
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Animals↗
Mechanisms of focal heat destruction of liver tumors.
BACKGROUND: Focal heat destruction has emerged as an effective treatment strategy in selected patients with malignant liver tumors. Radiofrequency ablation, interstitial laser thermotherapy, and microwave treatment are currently the most widely applied thermal ablative techniques. A major limitation of these therapies is incomplete tumor destruction and overall high recurrences. An understanding of the mechanisms of tissue injury induced by focal hyperthermia is essential to ensure more complete tumor destruction. Here, the currently available scientific literature concerning the underlying mechanisms involved in the destruction of liver tumors by focal hyperthermia is reviewed. METHODS: Medline was searched from 1960 to 2004 for literature regarding the use of focal hyperthermia for the treatment of liver tumors. All relevant literature was searched for further references. RESULTS: Experimental evidence suggests that focal hyperthermic injury occurs in two distinct phases. The first phase results in direct heat injury that is determined by the total thermal energy applied, tumor biology, and the tumor microenvironment. Tumors are more susceptible to heat injury than normal cells as the result of specific biological features, reduced heat dissipating ability, and lower interstitial pH. The second phase of hyperthermic injury is indirect tissue damage that produces a progression of tissue injury after the cessation of the initial heat stimulus. This progressive injury may involve a balance of several factors, including apoptosis, microvascular damage, ischemia-reperfusion injury, Kupffer cell activation, altered cytokine expression, and alterations in the immune response. Blood flow modulation and administration of thermosensitizing agents are two methods currently used to increase the extent of direct thermal injury. The processes involved in the progression of thermal injury and therapies that may potentially modulate them remain poorly understood. CONCLUSION: Focal hyperthermia for the treatment of liver tumors involves complex mechanisms. Evidence suggests that focal hyperthermia produces both direct and indirect tissue injury by differing underlying processes. Methods to enhance the effects of treatment to achieve complete tumor destruction should focus on manipulating these processes.
Animals↗
Cytokine expression by head and neck squamous cell carcinomas.
Cytokines are known to play an important role in host defense by regulating the function, growth, and differentiation of the cells of the immune system. We hypothesize that, in the tumor microenvironment, tumor cells and resident tissue cells (e.g., fibroblasts) also produce cytokines that may regulate the local immune response to tumors. Initially, homogenates of eight head and neck squamous cell carcinomas (HNSCC) were assayed for the presence of interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) to establish the presence of these cytokines in the tumors in vivo. We detected IL-1 in all tumor homogenates and IL-4, IL-6, and GM-CSF in some homogenates. To assess the ability of HNSCC to produce these cytokines, supernatants of short-term primary cultures of HNSCC were assayed for the same cytokines. No IL-1 was detected, although baseline levels of IL-4, IL-6, and GM-CSF were present. However, the stimulation of primary tumor cultures with exogenous IL-1 induced or significantly enhanced production of IL-4 (p < 0.01), IL-6 (p < 0.001), and GM-CSF (p < 0.02). These results support our hypothesis that HNSCC secrete cytokines that may influence the response of local immune cells. Our data also suggest that IL-1 may have a central role in regulating the local immune response through the enhancement or induction of cytokine production by tumor and/or resident tissue cells.
Carcinoma, Squamous Cell↗
Decreased expression of intercellular adhesion molecule-1 (ICAM-1) and urokinase-type plasminogen activator receptor (uPAR) is associated with tumor cell spreading in vivo.
The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1 (ICAM-1, 70.1 +/- 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 +/- 5.2%) positive cells, while a weak expression of MHC class II (IA, 2.2 +/- 0.2% and IE, 17.4 +/- 3.7%) and B7 (12.1 +/- 2.2%) antigens was detected. In our tumor experimental model, after implantation of tumor cells, visible tumor masses were present at days 5-7 with a relatively fast tumor growth until day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity may lead to a tumor invasive phenotype.
Animals↗
Stromal cell oxidation: a mechanism by which tumors obtain vitamin C.
Human tumors may contain high concentrations of ascorbic acid, but little is known about how they acquire the vitamin. Certain specialized cells can transport ascorbic acid directly through a sodium ascorbate cotransporter, but in most cells, vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. Mice with established hematopoietic and epithelial cell xenografts were studied for the accumulation of injected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epithelial tumor cell lines can only transport vitamin C in the oxidized form (dehydroascorbic acid) in vitro; however, when grown as xenografts in mice, they rapidly accumulated vitamin C after administration of radiolabeled ascorbic acid. The involvement of the GLUTs in vitamin C uptake by the xenografted tumors was demonstrated by competitive inhibition with D-glucose but not L-glucose. Because the malignant cells were not capable of directly transporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of vitamin C in animals injected with ascorbic acid was inhibited by coadministration of superoxide dismutase, implying a role for superoxide anion in the oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could not generate superoxide anion in culture, the minced xenograft tumors did. Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic acid by superoxide anion produced by cells in the tumor stroma as a mechanism for generating the transportable form of the vitamin.
Animals↗
In vitro demonstration of breast cancer tumor cell sub-populations based on interleukin-1/tumor necrosis factor induction of interleukin-8 expression.
Interleukin-8 (IL-8) has been identified as an angiogenesis factor (AF) as well as a tumor cell chemotactic factor and mitogen. Recent in vivo studies have demonstrated the expression of IL-8, IL-1 and TNF, as well their receptors, on various sub-populations of tumor cells in human breast cancer (HBC). Since pro-inflammatory cytokines such as IL-1 and TNF are known inducers of IL-8 in non-tumor cells, we hypothesize that IL-1/TNF may act as an IL-8 inducer in HBC, and thus enhance HBC tumor progression. To begin to test this hypothesis, we evaluated the ability of: a) human breast cancer cell lines (BCC) and normal human breast epithelial cell lines (BEC) to produce IL-8 in vitro; and b) IL-1 and TNF to regulate the expression of IL-8. In general, basal IL-8 expression was low in all 8 cell lines examined. TNF-alpha and TNF-beta induced a 3- to 24-fold increase in IL-8 protein expression of BEC, and a 2- to 8-fold increased IL-8 expression in estrogen-independent BCC cell lines and no significant IL-8 expression in estrogen-dependent cell lines. Conversely, IL-1alpha and IL-1beta, induced a 5- to 104-fold stimulation of BEC and a 330 to 1,138-fold increase in IL-8 expression in estrogen independent BCC. These observations demonstrate the ability of HBC cells to produce IL-8 in vitro and further indicate that IL-1 is a potent inducer of IL-8 expression by BEC and BCC. Furthermore, this in vitro data support the hypothesis, that within the HBC tumor microenvironment, tumor cells exist that respond to pro-inflammatory cytokine (IL-1) stimulation (i.e. MDA-MB-231) and those that do not (i.e. MCF-7). Additionally, HBC tumor cell lines that can be induced to express high levels of IL-8 tend to be associated with a more aggressive phenotype.
Antineoplastic Agents↗
Region-Resolved Integrative Multi-Omic Characterization Reveals Diverse Tumor and Microenvironment Features of Pituitary Neuroendocrine Tumors.
Pituitary neuroendocrine tumors are frequently invasive, with cavernous sinus invasion leading to poor treatment outcomes and high recurrence. Regional differences within these tumors remain poorly understood, hindering targeted therapy development. Here, we present the first integrative multi-omics analysis combining proteomics, metabolomics and single-cell transcriptomics to characterize tumors from the cavernous sinus and saddle regions. Our results reveal profound regional and cellular heterogeneity: cavernous sinus tumors exhibit significantly enhanced cell proliferation, driven by cancer-associated fibroblasts through the IGF1-IGF1R-MAPK1 axis. Cancer-associated fibroblasts in the cavernous sinus secrete IGF1 under regulation of the transcription factor FOXO1, which binds to receptors on tumor cells to activate proliferation. Metabolomic profiling identifies proline as a key enriched metabolite that stimulates cancer-associated fibroblasts to produce collagen fibers, reinforcing a pro-tumorigenic microenvironment. Single-cell transcriptomics further delineates a distinct subpopulation of receptor-positive malignant cells and a high abundance of cancer-associated fibroblasts in the cavernous sinus. These findings establish core mechanisms underlying the aggressive behavior of cavernous sinus-invading tumors, providing novel actionable targets for precision therapeutic strategies tailored to distinct tumor regions.
Humans↗
Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.
Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.
Humans↗
Effect of tumor host microenvironment on photodynamic therapy in a rat prostate tumor model.
PURPOSE: Tumor host microenvironment plays an important role in tumor growth, metastasis, and response to cancer therapy. In this study, the influence of tumor host environment on tumor pathophysiology, photosensitizer distribution, and photodynamic therapy (PDT) treatment effect was examined in the metastatic at lymph node and lung (MatLyLu) rat prostate tumor. EXPERIMENTAL DESIGN: MatLyLu tumors implanted in different host environment [i.e., orthotopically (in the prostate) or s.c.] were compared for difference in vessel density, average vessel size, vascular permeability, tumor vascular endothelial growth factor production, and tumor oxygenation. Uptake of photosensitizer verteporfin in tumors in both sites was determined by fluorescence microscopy. To compare tumor response to PDT, both orthotopic and s.c. MatLyLu tumors were given the same doses of verteporfin and laser light treatment, and PDT-induced tumor necrotic area was measured histologically. RESULTS: Orthotopic MatLyLu tumors were found to grow faster, have higher vessel density and more permeable vasculature, have higher vascular endothelial growth factor protein levels, and have lower tumor hypoxic fraction than the s.c. tumors. Uptake of photosensitizer verteporfin in the orthotopic tumor was higher than in the s.c. tumors at 15 minutes after injection (1 mg/kg, i.v.), and became similar at 3 hours after injection. For the vascular targeting PDT treatment (0.25 mg/kg verteporfin, 50 J/cm(2) at 50 mW/cm(2), 15 minutes drug-light interval), there was no significant difference in PDT-induced tumor necrotic area between the orthotopic and s.c. tumors, with 85% to 90% necrosis in both types of tumors. However, tumor necrosis induced by the cellular targeting PDT (1 mg/kg verteporfin, 50 J/cm(2) at 50 mW/cm(2), 3 hours drug-light interval) was significantly different in the orthotopic (64%) versus the s.c. (29%) tumors. CONCLUSIONS: Tumor host environment can significantly affect photosensitizer verteporfin distribution and PDT treatment effect. Verteporfin-PDT regimen targeting tumor cells is more sensitive to such influence than the vascular targeting PDT. Our study showed the importance of tumor host environment in determining tumor physiologic properties and tumor response to PDT. To obtain clinically relevant information, orthotopic tumor model should be used in the experimental studies.
Animals↗
Development and validation of a novel risk stratification signature derived from migrasome and tumor microenvironment-related genes for molecular subtyping and improving clinical outcomes in head and neck squamous cell carcinoma.
BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.
Humans↗
Tumor microenvironment-simulated organoids for personalized therapy prediction in head and neck squamous cell carcinoma.
Patient-derived organoids (PDOs) have emerged as promising models for predicting personalized drug responses in cancer therapy. However, the absence of essential immune and stromal components limits their ability to recapitulate the tumor microenvironment. Here, we established a total of 30 patient-derived organoids (PDOs) from 79 patients with locally advanced (LA) and recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). These PDOs maintained sustained expansion capacity and preserved the histopathological characteristics and genomic heterogeneity of their parental tumors. By integrating autologous immune cells and cancer-associated fibroblasts (CAFs) into PDOs, respectively, microenvironment-simulated PDOs (MS-PDOs) were established using a feasible co-culture condition. Compared with conventional PDOs, MS-PDOs-PBMC exhibited specific cytotoxicity and responses to PD-1/PD-L1 inhibitors, while MS-PDOs-CAFs showed enhanced tolerance to chemotherapy drugs, indicating that microenvironment components modulate therapeutic responses in HNSCC. The drug response profiles of MS-PDOs exhibited diverse sensitivity to PD-1/PD-L1 inhibitors, chemotherapy drugs, and combination regimens. Notably, the therapeutic predictions of MS-PDOs were consistent with clinical treatment outcomes, supporting their translational relevance. Collectively, MS-PDOs serve as a robust platform for modeling the tumor microenvironment and predicting therapeutic responses, supporting precision medicine-guided clinical decision-making and offering personalized treatment strategies for HNSCC patients.
Humans↗
Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment.
The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFalpha, and TGFbeta. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.
Journal Article↗
Tumor acidity, chemoresistance and proton pump inhibitors.
Tumor microenvironment may play a key role in tumor malignancy. It is hypothesized that hypoxia and acidity may contribute to the progression from benign to malignant growth. In particular, the unfavorable environment may induce the selection of tumor cells able to survive in acidic and hypoxic conditions. In fact, the common components of the cancer phenotype result from active selection, and characteristics of tumor microenvironment may create the best condition for this selection. Acidity, in particular, has been shown to have a role in resistance to chemotherapy, proliferation and metastatic behavior. In fact, a mechanism of resistance to cytotoxic drugs may be the alteration of the tumor microenvironment through changes of the pH gradient between the extracellular environment and cell cytoplasm. The extracellular pH of solid tumors is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumors. An important determinant of tumor acidity is the anaerobic metabolism that allows selection of cells able to survive in an hypoxic-anoxic environment with the generation of lactate. However, this is not the major mechanism responsible for the development of an acidic environment within solid tumors. It appears clear that a complex framework of protein-protein, protein-lipid and lipid-lipid interactions underlay the pH homeostasis in mammalian cells. Malignant tumor cells seem to hijack some of these mechanism to protect themselves from the acidic environment and to maintain acidity in an environment unsuitable for normal or more differentiated cells. Recent data suggest that vacuolar-type (V-type) H(+)-ATPases, that pump protons across the plasma membrane, may have a key role in the acidification of the tumor microenvironment. Some human tumor cells are characterized by an increased V-type H(+)-ATPase expression and activity, and pretreatment with proton pump inhibitors -- a class of H(+)-ATPase inhibitors -- sensitized tumor cell lines to the effect of a variety of anticancer drugs. Proton pump inhibitor pretreatment has been associated with inhibition of V-type H(+)-ATPase activity and increase in both extracellular pH and pH of lysosomal organelles. In vivo experiments in human/mouse xenografts have shown that oral pretreatment with proton pump inhibitors is able to sensitize human solid tumors to anticancer drugs. These data suggest that tumor alkalinization may represent a key target of future antitumor strategies.
Acid-Base Equilibrium↗
MicroRNA-486: a dual-function biomarker for diagnosis and tumor immune microenvironment characterization in non-small cell lung cancer.
BACKGROUND: This investigation evaluates the clinical significance and molecular mechanisms of microRNA-486 (miR-486) as a potential biomarker in non-small cell lung cancer (NSCLC) through an integrative analytical approach. METHODS: We conducted systematic search and meta-analysis of diagnostic studies from major biomedical databases from inception through April 04, 2025, followed by comprehensive bioinformatics interrogation. Protein-protein interaction (PPI) networks were constructed using STRING to identify key hub genes regulated by miR-486. Validation of hub genes employed TCGA datasets, while immune infiltration analysis utilized TIMER2.0 platform. RESULTS: The meta-analysis indicated that miR-486, both individually and in combination, could be effective biomarkers for NSCLC detection. Afterwards, functional enrichment analyses of miR-486 target genes highlighted significant ontology terms and pathways crucial to the initiation and progression of NSCLC. PPI networks revealed key proteins and modules that participate in multiple essential pathways associated with NSCLC pathogenesis. Furthermore, the identified hub genes were validated for differential expression in cancerous versus normal tissues, suggesting their potential diagnostic utility, while subsequent survival analyses confirmed their prognostic value through significant associations with overall survival. Notably, these hub genes were found to be significantly associated with immune infiltration levels, immune microenvironment scores, and immune-related proteins in NSCLC. CONCLUSIONS: This dual-modality investigation establishes miR-486 as a multi-functional biomarker in NSCLC, demonstrating both diagnostic utility and immunoregulatory potential through tumor microenvironment modulation.
Humans↗
The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression.
We have previously described the expression of interleukin cytokines (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) in human breast cancer (HBC) tissue. Based on our previous studies, we hypothesize that the IL-1 family of cytokines, antagonists (IL-1ra) and receptors (IL-1RI and IL-1RII) are present within the human breast cancer (HBC) tumor microenvironment and that the IL-1 network of cytokines and receptors within the tumor microenvironment can control tumor cell subpopulation expression of other protumorigenic cytokines such as the angiogenic/growth factor, interleukin-8 (IL-8). To test this hypothesis we characterized the in vivo expression of the IL-1 network in HBC tissues and homogenates by immunohistochemistry (IHC) and ELISA. Additionally, we examined IL-1R expression in HBC cell lines in vitro and in a murine xenograft model by IHC. Finally, we determined the ability of IL-1 to induce IL-8 expression in in vitro using HBC cell lines. We observed that not only are the IL-1 cytokines present in HBC tissue and homogenates, but that IL-1Rs and IL-8 are also present in the HBC tumor microenvironment. Additionally, expression levels for some members of the IL-1/IL-8 network of cytokines correlated with the prognostic indicators, ER/PR. Using HBC cell lines, we observed that HBC cell lines express IL-1Rs in vitro and in the xenograft model. Furthermore, in vitro, HBC cell lines show a spectrum of responsiveness to IL-1 as measured by expression the proangiogenic/mitogenic cytokine IL-8. Our data clearly demonstrate the presence and distribution of IL-1 cytokines and receptors in HBC and suggests that the local expression of IL-1 results in the activation of a population of cells within the HBC tumor microenvironment. This activation of the IL-1/IL-1R cytokine family via autocrine and/or paracrine mechanisms leads to a cascade of secondary protumorigenic cytokines. These secondary signals induce the expression of numerous protumorigenic activities such as the expression of IL-8, and subsequently contribute to angiogenesis, tumor proliferation, and tumor invasion.
Animals↗
Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress.
It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
Animals↗
Age and sex: dual drivers remodeling the anti-tumor immune microenvironment and shaping personalized immuno-oncology.
Despite breakthrough advancements in cancer immunotherapy, significant inter-individual heterogeneity in clinical outcomes persists, bringing the regulatory roles of intrinsic host biological variables into sharp focus. Accumulating fundamental and clinical evidence indicates that age and sex play crucial roles in determining tumor susceptibility, disease progression, and the remodeling of the anti-tumor immune microenvironment. This review systematically delineates the profound impacts of the dual dimensions of age and sex on anti-tumor immune responses and immune evasion mechanisms. In the dimension of age, this article outlines the progressive functional decline of T/B lymphocytes and innate immune subsets driven by immunosenescence, and emphatically reveals how inflammaging and its associated senescence-associated secretory phenotype (SASP) orchestrate the formation of an immunosuppressive tumor microenvironment. In the dimension of sex, we deeply explore four core mechanisms comprising sex chromosome genomics (e.g., escape from X-chromosome inactivation and loss of Y chromosome), sex hormone networks, microenvironmental metabolic reprogramming, and the host gut microbiome, elucidating the molecular basis driving the disparities in innate and adaptive immunity between males and females. In summary, thoroughly deciphering the complex immune regulatory networks driven by age and sex not only helps elucidate the disparities in efficacy and toxicity observed in patients undergoing immune checkpoint inhibitors, but also provides crucial theoretical foundations and translational insights for the future development of "age-tailored" and "sex-specific" strategies in personalized immuno-oncology.
Humans↗