bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–07–28
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities.
  2. Tumor associated macrophages in breast cancer progression: implications and clinical relevance.
  3. Tumor-associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire.
  4. Progression of m6A in the tumor microenvironment: hypoxia, immune and metabolic reprogramming.
  5. Exploiting the tumor microenvironment and tumor mechanobiology for the treatment of cancer cachexia.
  6. Immunotherapies Targeting Tumor-Associated Macrophages (TAMs) in Cancer.
  7. Unraveling the Immune Microenvironment in Diffuse Large B-Cell Lymphoma: Prognostic and Potential Therapeutic Implications.
  8. Myeloid-derived suppressor cells in the tumor microenvironment reduce uncoupling protein 1 expression to boost immunosuppressive activity.
  9. Revolutionizing Cancer Treatment: Unleashing the Power of Combining Oncolytic Viruses with CAR-T Cells.
  10. Potential applications of macrophages in cancer immunotherapy.
  11. Progress in reeducating tumor-associated macrophages in tumor microenvironment.
  12. Dysfunction of dendritic cells in tumor microenvironment and immunotherapy.
  13. The breast cancer tumor microenvironment and precision medicine: immunogenicity and conditions favoring response to immunotherapy.
  14. Uncovering Porphyrin Accumulation in the Tumor Microenvironment.
  15. Harnessing the tumor microenvironment to boost adoptive T cell therapy with engineered lymphocytes for solid tumors.
  16. Heterogeneity and function of cancer-associated fibroblasts in renal cell carcinoma.
  17. Potential role of ANGPTL4 in cancer progression, metastasis, and metabolism: a brief review.
  18. Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.
  19. Glioma-Associated Sialoglycans Drive the Immune Suppressive Phenotype and Function of Myeloid Cells.
  20. Targeting anticancer immunity in melanoma tumor microenvironment: Unleashing the potential of adjuvants, drugs, and phytochemicals.
  21. The Multifaceted Role of Neutrophils in NSCLC in the Era of Immune Checkpoint Inhibitors.
  1. Curr Oncol. 2024 Jul 01. 31(7): 3826-3844
    The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities.
    Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie M Ogilvie, Cielle Lockington, Duncan Petrik, Jan Soeren Eichhorn, Jim Petrik.
      The tumor microenvironment (TME) in ovarian cancer (OC) has much greater complexity than previously understood. In response to aggressive pro-angiogenic stimulus, blood vessels form rapidly and are dysfunctional, resulting in poor perfusion, tissue hypoxia, and leakiness, which leads to increased interstitial fluid pressure (IFP). Decreased perfusion and high IFP significantly inhibit the uptake of therapies into the tumor. Within the TME, there are numerous inhibitor cells, such as myeloid-derived suppressor cells (MDSCs), tumor association macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs) that secrete high numbers of immunosuppressive cytokines. This immunosuppressive environment is thought to contribute to the lack of success of immunotherapies such as immune checkpoint inhibitor (ICI) treatment. This review discusses the components of the TME in OC, how these characteristics impede therapeutic efficacy, and some strategies to alleviate this inhibition.
    Keywords:  immunosuppression; interstitial fluid pressure; ovarian cancer; tumor angiogenesis; tumor microenvironment; vascular normalization
    DOI:  https://doi.org/10.3390/curroncol31070283
  2. Front Immunol. 2024 ;15 1441820
    Tumor associated macrophages in breast cancer progression: implications and clinical relevance.
    Maria Stavrou, Anastasia Constantinidou.
      Macrophages represent an immune cell population characterized by high plasticity and a range of properties and functions. Their activation status and specific phenotype are highly associated with their localization and the environmental cues they receive. The roles of macrophages in cancer development are diverse. Despite their antitumor effects at early stages of the disease, their presence in the tumor microenvironment (TME) has been linked to tumor promotion upon disease establishment. Tumor associated macrophages (TAMs) are key components of breast cancer TME and they have been associated with poor clinical outcomes. High TAM densities were found to correlate with tumor progression, increased metastatic potential and poor prognosis. Interestingly, considerably higher levels of TAMs were found in patients with triple negative breast cancer (TNBC)-the most aggressive type of breast cancer-compared to other types. The present review summarizes recent findings regarding the distinct TAM subsets in the TME and TAM involvement in breast cancer progression and metastasis. It highlights the constant interplay between TAMs and breast cancer cells and its major contribution to the progression of the disease, including such aspects as, polarization of macrophages toward a tumor promoting phenotype, induction of epithelial to mesenchymal transition (EMT) in cancer cells and enhancement of cancer stem cell properties. Further, we discuss the clinical relevance of these findings, focusing on how a better delineation of TAM involvement in breast cancer metastasis will facilitate the selection of more efficient treatment options.
    Keywords:  breast cancer; metastasis; prognosis; surface markers; tumor associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1441820
  3. Cell Biol Int. 2024 Jul 25.
    Tumor-associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire.
    Shaivy Malik, Niti Sureka, Sana Ahuja, Durre Aden, Samreen Zaheer, Sufian Zaheer.
      The tumor microenvironment (TME) is a critical determinant in the initiation, progression, and treatment outcomes of various cancers. Comprising of cancer-associated fibroblasts (CAF), immune cells, blood vessels, and signaling molecules, the TME is often likened to the soil supporting the seed (tumor). Among its constituents, tumor-associated macrophages (TAMs) play a pivotal role, exhibiting a dual nature as both promoters and inhibitors of tumor growth. This review explores the intricate relationship between TAMs and the TME, emphasizing their diverse functions, from phagocytosis and tissue repair to modulating immune responses. The plasticity of TAMs is highlighted, showcasing their ability to adopt either protumorigenic or anti-tumorigenic phenotypes based on environmental cues. In the context of cancer, TAMs' pro-tumorigenic activities include promoting angiogenesis, inhibiting immune responses, and fostering metastasis. The manuscript delves into therapeutic strategies targeting TAMs, emphasizing the challenges faced in depleting or inhibiting TAMs due to their multifaceted roles. The focus shifts towards reprogramming TAMs to an anti-tumorigenic M1-like phenotype, exploring interventions such as interferons, immune checkpoint inhibitors, and small molecule modulators. Noteworthy advancements include the use of CSF1R inhibitors, CD40 agonists, and CD47 blockade, demonstrating promising results in preclinical and clinical settings. A significant section is dedicated to Chimeric Antigen Receptor (CAR) technology in macrophages (CAR-M cells). While CAR-T cells have shown success in hematological malignancies, their efficacy in solid tumors has been limited. CAR-M cells, engineered to infiltrate solid tumors, are presented as a potential breakthrough, with a focus on their development, challenges, and promising outcomes. The manuscript concludes with the exploration of third-generation CAR-M technology, offering insight into in-vivo reprogramming and nonviral vector approaches. In conclusion, understanding the complex and dynamic role of TAMs in cancer is crucial for developing effective therapeutic strategies. While early-stage TAM-targeted therapies show promise, further extensive research and larger clinical trials are warranted to optimize their targeting and improve overall cancer treatment outcomes.
    Keywords:  CAR‐M; monocyte; tumor microenvironment; tumour associated macrophages
    DOI:  https://doi.org/10.1002/cbin.12226
  4. Cell Death Discov. 2024 Jul 20. 10(1): 331
    Progression of m6A in the tumor microenvironment: hypoxia, immune and metabolic reprogramming.
    Xuan Han, Yu Zhu, Juan Ke, Yufeng Zhai, Min Huang, Xin Zhang, Hongjie He, Xiaojing Zhang, Xuehong Zhao, Kaikai Guo, Xianglin Li, Zhongyu Han, Yanming Zhang.
      Recently, N6-methyladenosine (m6A) has aroused widespread discussion in the scientific community as a mode of RNA modification. m6A comprises writers, erasers, and readers, which regulates RNA production, nuclear export, and translation and is very important for human health. A large number of studies have found that the regulation of m6A is closely related to the occurrence and invasion of tumors, while the homeostasis and function of the tumor microenvironment (TME) determine the occurrence and development of tumors to some extent. TME is composed of a variety of immune cells (T cells, B cells, etc.) and nonimmune cells (tumor-associated mesenchymal stem cells (TA-MSCs), cancer-associated fibroblasts (CAFs), etc.). Current studies suggest that m6A is involved in regulating the function of various cells in the TME, thereby affecting tumor progression. In this manuscript, we present the composition of m6A and TME, the relationship between m6A methylation and characteristic changes in TME, the role of m6A methylation in TME, and potential therapeutic strategies to provide new perspectives for better treatment of tumors in clinical work.
    DOI:  https://doi.org/10.1038/s41420-024-02092-2
  5. Ann Oncol. 2024 Jul 23. pii: S0923-7534(24)01495-9. [Epub ahead of print]
    Exploiting the tumor microenvironment and tumor mechanobiology for the treatment of cancer cachexia.
    Kostas A Papavassiliou, Athanasios G Papavassiliou.
      
    Keywords:  Cancer cachexia; Fibrosis; Inhibitors; Mechanosignaling; Targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.annonc.2024.07.721
  6. Pharmaceutics. 2024 Jun 27. pii: 865. [Epub ahead of print]16(7):
    Immunotherapies Targeting Tumor-Associated Macrophages (TAMs) in Cancer.
    Mei-Ye Li, Wei Ye, Ke-Wang Luo.
      Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy.
    Keywords:  TAMs; clinical application; polarization; therapies
    DOI:  https://doi.org/10.3390/pharmaceutics16070865
  7. Curr Issues Mol Biol. 2024 Jul 05. 46(7): 7048-7064
    Unraveling the Immune Microenvironment in Diffuse Large B-Cell Lymphoma: Prognostic and Potential Therapeutic Implications.
    Epameinondas Koumpis, Alexandra Papoudou-Bai, Konstantina Papathanasiou, Evangelos Kolettas, Panagiotis Kanavaros, Eleftheria Hatzimichael.
      Diffuse large B cell lymphoma (DLBCL) is a multifaceted condition characterized by significant diversity in its molecular and pathological subtypes and clinical manifestation. Despite the progress made in the treatment of DLBCL through the development of novel drugs, an estimated one-third of patients encounter relapse or acquire refractory disease. The tumor microenvironment (TME) of DLBCL, a complex network consisting of cellular and noncellular components that engage in interactions with the tumor, is a parameter that is gaining increasing attention. The TME comprises both the immune and nonimmune microenvironments. The immune microenvironment comprises natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, myeloid-derived suppressor cells (MDSCs), and T and B lymphocytes. The nonimmune microenvironment consists of the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells, and other molecules that are secreted. Despite ongoing research, the exact impact of these components and their interaction on the progression of the disease remains elusive. A comprehensive review of significant discoveries concerning the cellular and noncellular constituents, molecular characteristics, and treatment response and prognosis of the TME in DLBCL, as well as the potential targeting of the TME with novel therapeutic approaches, is provided in this article.
    Keywords:  DLBCL; TME; lymphoma; microenvironment
    DOI:  https://doi.org/10.3390/cimb46070420
  8. Biochem Biophys Res Commun. 2024 Jul 19. pii: S0006-291X(24)00944-6. [Epub ahead of print]732 150408
    Myeloid-derived suppressor cells in the tumor microenvironment reduce uncoupling protein 1 expression to boost immunosuppressive activity.
    Jianghua Zhao, Min Gu, Yu Zhang, Xiaoqin Jia, Weiming Xiao, Guotao Lu, Weiwei Chen, Weijuan Gong.
      Uncoupling protein 1 (UCP1) is located at the inner membrane of mitochondria and mediates nonshivering thermogenesis. Its abnormal expression is associated with metabolic diseases, cancer, and acute kidney injury. Myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity accumulate in the tumor microenvironment (TME). Here, decreased UCP1 expression in MDSCs was observed in the peripheral blood of patients with colorectal cancer and transplanted mouse tumors. Aggravated tumor progression was observed in UCP1-knockout mice and conditional knockout mice (UCP1fl/fl-S100A8cre). The number of G-MDSCs and M-MDSCs increased in the transplanted tumor tissues from UCP1-deficient mice compared with those from wild-type mice. The tumor-promoting effect disappeared when the tumor-bearing mice were depleted of MDSCs by the α-DR5 administration. Adoptive transfer of tumor-derived MDSCs sharply promoted the tumor growth in vivo. Furthermore, these tumor-derived MDSCs enhanced the proliferation, reduced death, inhibited IFN-γ production of CD4+ and CD8+T cells, and induced Treg cells ex vivo. In conclusion, MDSCs in the TME alter the metabolic pattern by decreasing UCP1 expression to enhance immunosuppressive activity for tumor escape.
    Keywords:  Immunosuppression; MDSCs; Tumor; UCP1
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150408
  9. Anticancer Agents Med Chem. 2024 Jul 24.
    Revolutionizing Cancer Treatment: Unleashing the Power of Combining Oncolytic Viruses with CAR-T Cells.
    Lin Zhang, Shuxian Guo, ShuYing Chang, Guan Jiang.
      Oncolytic Viruses (OVs) have emerged as a promising treatment option for cancer thanks to their significant research potential and encouraging results. These viruses exert a profound impact on the tumor microenvironment, making them effective against various types of cancer. In contrast, the efficacy of Chimeric antigen receptor (CAR)-T cell therapy in treating solid tumors is relatively low. The combination of OVs and CAR-T cell therapy, however, is a promising area of research. OVs play a crucial role in enhancing the tumor-suppressive microenvironment, which in turn enables CAR-T cells to function efficiently in the context of solid malignancies. This review aims to provide a comprehensive analysis of the benefits and drawbacks of OV therapy and CAR-T cell therapy, with a focus on the potential of combining these two treatment approaches.
    Keywords:  CAR-T cells; Oncolytic virus; cancer; combination therapy; immunoreaction.; tumor microenvironment
    DOI:  https://doi.org/10.2174/0118715206308253240723055019
  10. Biomed Pharmacother. 2024 Jul 23. pii: S0753-3322(24)01045-X. [Epub ahead of print]178 117161
    Potential applications of macrophages in cancer immunotherapy.
    Maryam Sadri, Sahel Heidari, Arezoo Faridzadeh, Mona Roozbehani, Shirin Toosi, Reihaneh Alsadat Mahmoudian, Akram Hoseinzadeh, Mohammad Taha Salmani Fard, Fahimeh Lavi Arab, Soheil Rahmani Fard, Fatemeh Faraji.
      Immunotherapy has improved cancer treatment based on investigations of tumor immune escape. Manipulation of the immune system stimulates antitumor immune responses and blocks tumor immune escape routes. Genetically adoptive cell therapy, such as T cells, has yielded promising results for hematologic malignancies, but their application to solid tumors has been challenging. Macrophages have a wide broad of capabilities in regulating immune responses, homeostasis, and tissue development, as well as the ability to phagocyte, present antigens, and infiltrate the tumor microenvironment (TME). Given the importance of macrophages in cancer development, they could serve as novel tool for tumor treatment. Therefore, macrophages are used in different formats for direct and indirect targeting of tumor cells. This review summarized the available data on the various applications of macrophages in cancer immunotherapy.
    Keywords:  CAR-macrophage; CRISPRed macrophage; Cancer; Immunotherapy; Macrophage
    DOI:  https://doi.org/10.1016/j.biopha.2024.117161
  11. Discov Oncol. 2024 Jul 26. 15(1): 312
    Progress in reeducating tumor-associated macrophages in tumor microenvironment.
    Yiming Zhao, Qianyang Ni, Weijian Zhang, Suyang Yu.
      Malignant tumor, one of the most threatening diseases to human health, has been comprehensively treated with surgery, radiotherapy, chemotherapy and targeted therapy, but the prognosis has not always been ideal. In the past decade, immunotherapy has shown increased efficacy in tumor treatment; however, for immunotherapy to achieve its fullest potential, obstacles are to be conquered, among which tumor microenvironment (TME) has been widely investigated. In remodeling the tumor immune microenvironment to inhibit tumor progression, macrophages, as the most abundant innate immune population, play an irreplaceable role in the immune response. Therefore, how to remodel TME and alter the recruitment and polarization status of tumor-associated macrophages (TAM) has been of wide interest. In this context, nanoparticles, photodynamic therapy and other therapeutic approaches capable of affecting macrophage polarization have emerged. In this paper, we categorize and organize the existing means and methods for reprogramming TAM to provide ideas for clinical application of novel tumor-related therapies.
    Keywords:  Macrophage polarization; Nanoparticles; Photodynamic therapy; Tumor-associated macrophages; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s12672-024-01186-8
  12. Cancer Commun (Lond). 2024 Jul 25.
    Dysfunction of dendritic cells in tumor microenvironment and immunotherapy.
    Jie Chen, Yuhang Duan, Junye Che, Jianwei Zhu.
      Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.
    Keywords:  DCs immunotherapy; dendritic cells; dysfunction of DCs; tumor microenvironment
    DOI:  https://doi.org/10.1002/cac2.12596
  13. J Natl Cancer Cent. 2024 Mar;4(1): 14-24
    The breast cancer tumor microenvironment and precision medicine: immunogenicity and conditions favoring response to immunotherapy.
    Andrea Nicolini, Paola Ferrari, Roberto Silvestri, Federica Gemignani.
      Some main recent researches that have dissected tumor microenvironment (TME) by imaging mass cytometry (IMC) in different subtypes of primary breast cancer samples were considered. The many phenotypic variants, clusters of epithelial tumor and immune cells, their structural features as well as the main genetic aberrations, sub-clonal heterogeneity and their systematic classification also have been examined. Mutational evolution has been assessed in primary and metastatic breast cancer samples. Overall, based on these findings the current concept of precision medicine is questioned and challenged by alternative therapeutic strategies. In the last two decades, immunotherapy as a powerful and harmless tool to fight cancer has received huge attention. Thus, the tumor immune microenvironment (TIME) composition, its prognostic role for clinical course as well as a novel definition of immunogenicity in breast cancer are proposed. Investigational clinical trials carried out by us and other findings suggest that G0-G1 state induced in endocrine-dependent metastatic breast cancer is more suitable for successful immune manipulation. Residual micro-metastatic disease seems to be another specific condition that can significantly favor the immune response in breast and other solid tumors.
    Keywords:  Breast cancer; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jncc.2024.01.004
  14. Genes (Basel). 2024 Jul 22. pii: 961. [Epub ahead of print]15(7):
    Uncovering Porphyrin Accumulation in the Tumor Microenvironment.
    Swamy R Adapa, Abdus Sami, Pravin Meshram, Gloria C Ferreira, Rays H Y Jiang.
      Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be precisely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed "Porphyrin Overdrive". Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME's stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.
    Keywords:  cancer-associated fibroblasts; heme; porphyrin; protoporphyrin IX; tumor microenvironment
    DOI:  https://doi.org/10.3390/genes15070961
  15. Semin Immunopathol. 2024 Jul 25. 46(3-4): 8
    Harnessing the tumor microenvironment to boost adoptive T cell therapy with engineered lymphocytes for solid tumors.
    Martina Spiga, Elisa Martini, Maria Chiara Maffia, Fabio Ciceri, Eliana Ruggiero, Alessia Potenza, Chiara Bonini.
      Adoptive cell therapy (ACT) using Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) engineered T cells represents an innovative therapeutic approach for the treatment of hematological malignancies, yet its application for solid tumors is still suboptimal. The tumor microenvironment (TME) places several challenges to overcome for a satisfactory therapeutic effect, such as physical barriers (fibrotic capsule and stroma), and inhibitory signals impeding T cell function. Some of these obstacles can be faced by combining ACT with other anti-tumor approaches, such as chemo/radiotherapy and checkpoint inhibitors. On the other hand, cutting edge technological tools offer the opportunity to overcome and, in some cases, take advantage of TME intrinsic characteristics to boost ACT efficacy. These include: the exploitation of chemokine gradients and integrin expression for preferential T-cell homing and extravasation; metabolic changes that have direct or indirect effects on TCR-T and CAR-T cells by increasing antigen presentation and reshaping T cell phenotype; introduction of additional synthetic receptors on TCR-T and CAR-T cells with the aim of increasing T cells survival and fitness.
    DOI:  https://doi.org/10.1007/s00281-024-01011-y
  16. J Natl Cancer Cent. 2023 Jun;3(2): 100-105
    Heterogeneity and function of cancer-associated fibroblasts in renal cell carcinoma.
    Haijia Tang, Wenhao Xu, Jiahe Lu, Aihetaimujiang Anwaier, Dingwei Ye, Hailiang Zhang.
      With the advancement of anticancer therapy, there is increasing interest in understanding the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) play a pivotal role in the TME and have been the focus of much research in recent years. CAFs play an active role in cancer progression through complex interactions with other cells in the TME, releasing regulatory factors, synthesizing and remodeling the extracellular matrix. However, research on the role of CAFs in renal cell carcinoma (RCC) is still in its nascent stages. Here, we describe the origins and subgroups of CAFs, the roles of CAFs in the development and progression of RCC, the impact of CAFs on RCC prognosis, and the potential of CAFs as treatment targets in RCC. By analyzing CAF subsets, biomarkers, and targeted therapies, we present the significance and contribution of CAFs in RCC research. Furthermore, we highlight the distinct contribution of CAFs in advanced RCC through horizontal comparison with other cancers. This paper provides a comprehensive perspective of recent and foundational studies on the role of CAFs in RCC and other types of cancers and new insights for further study of CAFs in RCC.
    Keywords:  Cancer-associated fibroblasts; Renal cell carcinoma; Tumor heterogeneity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jncc.2023.04.001
  17. BMB Rep. 2024 Jul 24. pii: 6266. [Epub ahead of print]
    Potential role of ANGPTL4 in cancer progression, metastasis, and metabolism: a brief review.
    Min Seok Park, Sang Eun Kim, Pureunchowon Lee, Ju-Hee Lee, Kyung Hee Jung, Soon-Sun Hong.
      Angiopoietin-like 4 (ANGPTL4) has been identified as an adipokine involved in several non-metabolic and metabolic diseases, including angiogenesis, glucose homeostasis, and lipid metabolism. To date, the role of ANGPTL4 in cancer growth and progression, and metastasis, has been variable. Accumulating evidence suggests that proteolytic processing and posttranslational modifications of ANGPTL4 can significantly alter its function, and may contribute to the multiple and conflicting roles of ANGPTL4 in a tissue-dependent manner. With the growing interest in ANGPTL4 in cancer diagnosis and therapy, we aim to provide an up-to-date review of the implications of ANGPTL4 as a biomarker/oncogene in cancer metabolism, metastasis, and the tumor microenvironment (TME). In cancer cells, ANGPTL4 plays an important role in regulating metabolism by altering intracellular glucose, lipid, and amino acid metabolism. We also highlight the knowledge gaps and future prospect of ANGPTL4 in lymphatic metastasis and perineural invasion through various signaling pathways, underscoring its importance in cancer progression and prognosis. Through this review, a better understanding of the role of ANGPTL4 in cancer progression within the TME will provide new insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4.
  18. Endocrinology. 2024 Jul 23. pii: bqae092. [Epub ahead of print]
    Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.
    Caroline H Diep, Angela Spartz, Thu H Truong, Amy R Dwyer, Dorraya El-Ashry, Carol A Lange.
      Breast cancer progression involves intricate interactions between cancer cells and the tumor microenvironment (TME). This study elucidates the critical role of progesterone receptor (PR) signaling in mediating the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) on estrogen receptor-positive (ER+) luminal breast cancer cells. We demonstrate that CAFs produce physiologically relevant levels of estrogen and progesterone, which significantly contribute to breast cancer tumorigenicity. Specifically, CAF-conditioned media promoted PR-dependent anchorage-independent growth, tumorsphere formation/stem cell expansion, and CD44 upregulation. CAF cells formed co-clusters more frequently with PR+ breast cancer cells relative to PR-null models. While both PR isoforms mediated these actions, PR-A was a dominant driver of tumorsphere formation/stemness, while PR-B induced robust CD44 expression and CAF/tumor cell co-cluster formation. CD44 knockdown impaired CAF/tumor cell co-clustering. Fibroblast growth factor 2 (FGF2), also secreted by CAFs, phosphorylated PR (Ser294) in a MAPK-dependent manner and activated PR to enhance CD44 expression and breast cancer tumorigenicity. The FGFR inhibitor, PD173074, diminished CAF- and FGF2-dependent PR activation, tumorsphere formation, and co-clustering. In summary, this study reveals a novel mechanism through which stromal CAFs orchestrate elevated PR signaling in ER+ luminal breast cancer via secretion of both progesterone and FGF2, a potent activator of ERK1/2. Understanding tumor cell/TME interactions provides insights into potential therapeutic strategies aimed at disrupting PR- and/or FGF2/FGFR-dependent signaling pathways to prevent early metastasis in ER+ breast cancer patients.
    Keywords:  CAF; FGF2; PD173074; breast cancer; progesterone
    DOI:  https://doi.org/10.1210/endocr/bqae092
  19. Pharmaceutics. 2024 Jul 19. pii: 953. [Epub ahead of print]16(7):
    Glioma-Associated Sialoglycans Drive the Immune Suppressive Phenotype and Function of Myeloid Cells.
    Lenneke A M Cornelissen, Kim C M Santegoets, Esther D Kers-Rebel, Sandra A J F H Bossmann, Mark Ter Laan, Daniel Granado, Gosse J Adema.
      The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec-Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec-Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome.
    Keywords:  Siglecs; glioma; myeloid cells; sialoglycans
    DOI:  https://doi.org/10.3390/pharmaceutics16070953
  20. J Drug Target. 2024 Jul 23. 1-39
    Targeting anticancer immunity in melanoma tumor microenvironment: Unleashing the potential of adjuvants, drugs, and phytochemicals.
    Jingping Wang, Yaping Wang, Xiaofang Jiang.
      Melanoma poses a challenge in oncology because of its aggressive nature and limited treatment modalities. The tumor microenvironment (TME) in melanoma contains unique properties such as an immunosuppressive and high-density environment, unusual vasculature, and a high number of stromal and immunosuppressive cells. In recent years, numerous experiments have focused on boosting the immune system to effectively remove malignant cells. Adjuvants, consisting of phytochemicals, toll-like receptor (TLR) agonists, and cytokines, have shown encouraging results in triggering antitumor immunity and augmenting the therapeutic effectiveness of anticancer therapy. These adjuvants can stimulate the maturation of dendritic cells (DCs) and infiltration of cytotoxic CD8+ T lymphocytes (CTLs). Furthermore, nanocarriers can help to deliver immunomodulators and antigens directly to the tumor stroma, thereby improving their efficacy against malignant cells. The remodeling of melanoma TME utilizing phytochemicals, agonists, and other adjuvants can be combined with current modalities for improving therapy outcomes. This review article explores the potential of adjuvants, drugs, and their nanoformulations in enhancing the anticancer potency of macrophages, CTLs, and natural killer (NK) cells. Additionally, the capacity of these agents to repress the function of immunosuppressive components of melanoma TME, such as immunosuppressive subsets of macrophages, stromal and myeloid cells will be discussed.
    Keywords:  Adjuvants; Melanoma; Nanoparticles; Phytochemicals; TLR agonists; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1080/1061186X.2024.2384071
  21. Cancers (Basel). 2024 Jul 10. pii: 2507. [Epub ahead of print]16(14):
    The Multifaceted Role of Neutrophils in NSCLC in the Era of Immune Checkpoint Inhibitors.
    Shucheng Miao, Bertha Leticia Rodriguez, Don L Gibbons.
      Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, we summarize the current studies of neutrophil interaction with malignant cells, T-cells, and other components in the TME. Ongoing clinical trials are aimed at utilizing reagents that have putative effects on tumor-associated neutrophils, in combination with ICI. Elevated neutrophil populations and neutrophil-associated factors could be potential therapeutic targets to enhance anti-PD1 treatment in NSCLC.
    Keywords:  immunotherapy; neutrophils; non-small-cell lung cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16142507
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