Favor Tumor Progression Research Articles

Prognostic Utility of Autophagy Marker Beclin1 in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Autophagy is involved in several critical cellular processes regulating cell survival and death. Past research suggests that it may either act as a tumor suppressor or promote tumor progression. The purpose of this systematic review and meta-analysis was to evaluate the clinical and prognostic utility of a significant autophagy related protein-Beclin1, in oral squamous cell carcinoma (OSCC). Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed. Relevant literature was retrieved from PubMed, ScienceDirect and Google Scholar database. After removal of duplicates quality of the studies was assessed using Newcastle-Ottawa Scale. Heterogeneity was assessed using I2 index. Random effect model was used if I2 was more than 50% else fixed effect model was selected. Meta-analysis was carried out using Review Manager (RevMan; Version 5.4). Five studies with 494 cases were included in this meta-analysis. Beclin1 expression in OSCC was not significantly associated (p > 0.05) with gender, age, tumor size, lymph node metastasis, histological differentiation and overall survival. Nevertheless, a trend for low Beclin1 expression favoring tumor progression was observed. Sensitivity analysis revealed significant nodal positivity related to low Beclin1 expression. This study provided an overview of Beclin1 expression in OSCC and highlighted additional evaluations while its use as a prognostic marker. It is suggested that future studies should assess both nuclear as well as cytoplasmic expression of Beclin1 and report intra- and inter-tumor variations in its expression relating to clinicopathological parameters.

The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities.

Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.

Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions.

Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis

BackgroundColorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is...

Prognostic Value of PlGF Upregulation in Prostate Cancer.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management.

Exosomal miR-4745-5p/3911 from N2-polarized tumor-associated neutrophils promotes gastric cancer metastasis by regulating SLIT2

Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-κB pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.

Analysis of the expression of cytokines and chemokines, platelet-leukocyte aggregates, sCD40L and sCD62P in cutaneous melanoma.

Cutaneous melanoma (CM) is a malignancy with a variable incidence worldwide and a poor advanced-stage prognosis. Melanoma growth is closely associated with the immune system. A cross-sectional study was performed on CM patients admitted at the Hospital de Cancer de Pernambuco (HCP) between 2015 and 2018. Fifty-one CM patients were included, and 30 healthy individuals. The study aimed to evaluate the association of platelet activation mechanisms and inflammatory response in patients with cutaneous melanoma. Elevated serum IL10 and low serum TNF levels in CM patients compared to controls (p < 0.05). High IL6 levels in patients with negative lymph nodes LN (-) compared to positive lymph nodes group (LN +, p = 0.0005). Low RANTES levels in patients compared to controls (p < 0.05). Elevated levels of platelet-lymphocyte (PLA), platelet-monocytes (PMA), and platelet-neutrophils (PNA) aggregates were observed in patients compared to controls (p < 0.05). CM patients with stage II had lower PMA levels than stages I and III (p < 0.05). High PMA levels were observed in patients with LN (+) compared to the LN (-) group (p < 0.0001). Patients with SSM had high levels of sCD40L and sCD62P compared to controls (p < 0.05)). High sCD40L levels in stage II compared to the stage III group, and sCD62P in stages I and II compared to the stage III group (p < 0.05). High sCD62P levels in patients with LN (-) compared to the group LN (+) (p < 0.05). It was observed the immunosuppressive profile in CM may favor tumor progression. High levels of platelet-leukocyte aggregates, sCD40L, and sCD62P may be associated with the worst prognosis.

Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH.

Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy.

Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component.

Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.

Lymphatic endothelial cell-mediated accumulation of CD177+Treg cells suppresses antitumor immunity in human esophageal squamous cell carcinoma

ABSTRACT Regulatory T (Treg) cells are critical in shaping an immunosuppressive microenvironment to favor tumor progression and resistance to therapies. However, the heterogeneity and function of Treg cells in esophageal squamous cell carcinoma (ESCC) remain underexplored. We identified CD177 as a tumor-infiltrating Treg cell marker in ESCC. Interestingly, expression levels of CD177 and PD-1 were mutually exclusive in tumor Treg cells. CD177+ Treg cells expressed high levels of IL35, in association with CD8+ T cell exhaustion, whereas PD-1+ Treg cells expressed high levels of IL10. Pan-cancer analysis revealed that CD177+ Treg cells display increased clonal expansion compared to PD-1+ and double-negative (DN) Treg cells, and CD177+ and PD-1+ Treg cells develop from the same DN Treg cell origin. Importantly, we found CD177+ Treg cell infiltration to be associated with poor overall survival and poor response to anti-PD-1 immunotherapy plus chemotherapy in ESCC patients. Finally, we found that lymphatic endothelial cells are associated with CD177+ Treg cell accumulation in ESCC tumors, which are also decreased after anti-PD-1 immunotherapy plus chemotherapy. Our work identifies CD177+ Treg cell as a tumor-specific Treg cell subset and highlights their potential value as a prognostic marker of survival and response to immunotherapy and a therapeutic target in ESCC.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten–eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

B10 cells: Development, phenotype, and function in cancer.

B10 cells, a specialized subset of regulatory B cells, have been identified in both mice and humans. These cells are characterized by their regulatory impact on immune dynamics, principally through their secretion of interleukin-10 (IL-10), a cytokine known for its anti-inflammatory properties. The pivotal role of immune mediators such as B10 cells is to maintain a delicate equilibrium between antitumor immunity and tumor-promoting responses. Emerging studies have cast B10 cells as key suppressors in the antitumor immune arsenal. They operate in synergy with a spectrum of immune cells within the innate and adaptive spectrums, contributing to a milieu that favors tumor progression and metastatic spread. In this comprehensive review, we will discuss the ontogeny, phenotype and effector functions of B10 cells in murine systems. We will also review the role of B10 cells in oncological models in animal studies and extend these findings to the human clinical context, elucidating their role in facilitating tumor immune evasion. A thorough understanding of these processes is imperative for the strategic targeting and attenuation of B10 cell activity, which is anticipated to be a cornerstone in the advancement of effective cancer immunotherapy strategies.

EP2 and EP4 blockade prevents tumor-induced suppressive features in human monocytic myeloid-derived suppressor cells.

Tumors educate their environment to prime the occurrence of suppressive cell subsets, which enable tumor evasion and favors tumor progression. Among these, there are the myeloid-derived suppressor cells (MDSCs), their presence being associated with the poor clinical outcome of cancer patients. Tumor-derived prostaglandin E2 (PGE2) is known to mediate MDSC differentiation and the acquisition of pro-tumor features. In myeloid cells, PGE2 signaling is mediated via E-prostanoid receptor type 2 (EP2) and EP4. Although the suppressive role of PGE2 is well established in MDSCs, the role of EP2/4 on human MDSCs or whether EP2/4 modulation can prevent MDSCs suppressive features upon exposure to tumor-derived PGE2 is poorly defined. In this study, using an in vitro model of human monocytic-MDSCs (M-MDSCs) we demonstrate that EP2 and EP4 signaling contribute to the induction of a pro-tumor phenotype and function on M-MDSCs. PGE2 signaling via EP2 and EP4 boosted M-MDSC ability to suppress T and NK cell responses. Combined EP2/4 blockade on M-MDSCs during PGE2 exposure prevented the occurrence of these suppressive features. Additionally, EP2/4 blockade attenuated the suppressive phenotype of M-MDSCs in a 3D coculture with colorectal cancer patient-derived organoids. Together, these results identify the role of tumor-derived PGE2 signaling via EP2 and EP4 in this human M-MDSC model, supporting the therapeutic value of targeting PGE2-EP2/4 axis in M-MDSCs to alleviate immunosuppression and facilitate the development of anti-tumor immunity.

From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy.

Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are oftenundervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating onexciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions.

Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors.

Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.

Case report: Pediatric acute lymphoblastic leukemia with trisomy 5 as sole cytogenetic abnormality

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood and represents about 75 -80% of ALL in pediatric age group. ALL is characterised by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors and replacing the bone marrow elements and other lymphoid organs by leukemic cells (ALL blasts). The 5 year survival rate for childhood ALL is about 90% overall, children in lower risk groups have a better prognosis than those in higher risk group. Risk assessment is mainly based on cytogenetic and molecular factors in addition, clinical symptoms and signs, White blood cell count at diagnosis are all recognized for stratification. In present case the cytogenetic analysis showed the presence of trisomy 5 as a sole numerical abnormality. Trisomy 5 accounts for aneuploidy change in the cytogenetic analysis. The gain or loss of whole chromosome, ie aneuploidy is a major genomic insult in human cancers. Aneuploidy is observed in ~90% of solid tumors and~60% of hematological maignancies. The increased gene expression in trisomy 5 causes chromosomal instability (CIN), microsatellite instability (MIN) and genomic instabilty which inturn causes the cancer genome to undergo evolution, adaptation and favors tumor progression in patients with B cell acute lymphoblastic leukemia.

Abstract B005: Molecular, metabolic and functional CD4 T cell paralysis in lymph node impedes tumor control

Abstract Introduction: CD4 T cells are important in anti-tumor immunity, yet the regulation of CD4 tumor-specific T (TTS) cells during cancer development is still unclear. So far, studies have primarily focused on studying bulk CD4 tumor-infiltrating lymphocytes (TILs) with unknown antigen specificities, or transferring in vitro activated CD4 T cells as adoptive cell therapy (ACT), which fail to directly address how naïve CD4 TTS cells are activated and then differentiate in vivo in response to tumor progression. Therefore, studies addressing these questions will be critical to understand the state of anti-tumor CD4 T cells available for restorative therapies. Methods: To address these key questions, we developed two murine tumor cell lines, PyMG (an orthotopic breast tumor) and MC38GP (an adenocarcinoma tumor) expressing the LCMV glycoprotein 1-100 sequence (LCMV-GP1-100). The sequence contains an MHCII-epitope GP61-80 and an MHCI-epitope GP33-43, that can be recognized by TCR transgenic CD4 T cells (SMARTAs) and CD8 T cells (P14s), enabling direct in vivo identification of CD4 TTS cells. Results: We demonstrate that following tumor initiation, CD4 TTS cells are initially primed in the tumor draining lymph node (dLN), but rapidly frozen into a “paralyzed” state. The paralyzed state freezes CD4 TTS cell clonal expansion, impairs differentiation, limits IFNγ production, and redirects metabolic circuits, which together impede tumor control. Transcriptional programming of CD4 TTS cell paralysis is unique to the tumor setting and distinct from well-defined effector and exhaustion programming. In comparison, CD8 TTS cells do not manifest the proliferation defect. Paralysis is actively maintained throughout cancer progression by a functional interplay of regulatory T cells (Tregs) and CTLA4. Depleting Tregs induces robust proliferation of CD4 TTS cells, yet concurrently pushes the proliferated cells to become highly suppressive tumor-specific induced Tregs (iTregs). The differentiation of iTregs is dependent on the CTLA4 expression on CD4 TTS cells. Alleviating suppressive signals from both Tregs and CTLA4 is required to restore CD4 TTS cells proliferation, reduce iTreg differentiation and promote T helper cell differentiation. Overcoming CD4 TTS cell paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTS cells to favor tumor progression. Conclusion: Our study demonstrates that during early stages of cancer, the CD4 TTS cell development is quickly paralyzed at multiple levels of functional development. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTS cells to favor tumor progression. Citation Format: Mengdi Guo, Diala Abd-Rabbo, Bruna Bertol, Madeleine Carew, David G Brooks. Molecular, metabolic and functional CD4 T cell paralysis in lymph node impedes tumor control [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B005.

Lipocalin-2: A Nurturer of Tumor Progression and a Novel Candidate for Targeted Cancer Therapy

Within the tumor microenvironment (TME) exists a complex signaling network between cancer cells and stromal cells, which determines the fate of tumor progression. Hence, interfering with this signaling network forms the basis for cancer therapy. Yet, many types of cancer, in particular, solid tumors, are refractory to the currently used treatments, so there is an urgent need for novel molecular targets that could improve current anti-cancer therapeutic strategies. Lipocalin-2 (Lcn-2), a secreted siderophore-binding glycoprotein that regulates iron homeostasis, is highly upregulated in various cancer types. Due to its pleiotropic role in the crosstalk between cancer cells and stromal cells, favoring tumor progression, it could be considered as a novel biomarker for prognostic and therapeutic purposes. However, the exact signaling route by which Lcn-2 promotes tumorigenesis remains unknown, and Lcn-2-targeting moieties are largely uninvestigated. This review will (i) provide an overview on the role of Lcn-2 in orchestrating the TME at the level of iron homeostasis, macrophage polarization, extracellular matrix remodeling, and cell migration and survival, and (ii) discuss the potential of Lcn-2 as a promising novel drug target that should be pursued in future translational research.

SCF and IL-33 regulate mouse mast cell phenotypic and functional plasticity supporting a pro-inflammatory microenvironment

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). Several recent findings support their contribution to the transition from chronic inflammation to cancer. However, MC-derived mediators can either favor tumor progression, inducing the spread of the tumor, or exert anti-tumorigenic functions, limiting tumor growth. This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions. Thus, the exact effect of unique MC subset(s) during tumor progression is far from being understood. Using a murine model of colitis-associated colorectal cancer, we initially characterized the MC population within the TME and in non-lesional colonic areas, by multicolor flow cytometry and confocal microscopy. Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α. This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor. Thus, we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines. Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-α maintains a pro-inflammatory microenvironment.

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons.

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.