Search Results (11)

Breast cancer (BC) poses a significant clinical challenge due to late metastatic recurrence, driven by dormant disseminated tumor cells (DTCs). This review emphasizes the urgency of addressing tumor dormancy to reduce metastatic relapse, a major contributor to BC mortality. DTCs evade conventional therapies and immune surveillance, reactivating unpredictably, thus necessitating targeted strategies. Current research is fragmented, with conflicting data, inadequate models, and a lack of biomarkers hindering progress. This review synthesizes these gaps and proposes actionable priorities, advocating for integrated, standardized approaches. It highlights the roles of single-cell multi-omics, spatial transcriptomics, and humanized long-term models in unraveling dormancy mechanisms. The review also emphasizes macrophage-targeted therapies, dormancy-specific trials, and biomarker validation, offering paths to clinical translation. Ultimately, this work emphasizes the urgent need for integrated multi-omics approaches, including single-cell and spatial transcriptomics, combined with advanced computational analysis. Moreover, this review critically analyzes the existing research landscape, meticulously identifying key gaps, and proposing concrete, forward-looking directions for both fundamental research and clinical translation in the challenging field of BC dormancy. Full article

Neutrophils, accounting for 50–70% of circulating leukocytes, exhibit remarkable plasticity in tumor biology. Depending on tumor type and microenvironmental cues, they can exert either anti-tumor or pro-tumor effects. During tumor initiation, neutrophils exposed to chronic inflammation secrete cytokines and oncogenic microRNAs that promote genomic instability and malignant transformation. In tumor progression, neutrophils adopt context-dependent phenotypes and execute diverse functions, including polarization into anti-tumor (N1) or pro-tumor (N2) subsets; secretion of inflammatory and angiogenic mediators; formation of neutrophil extracellular traps (NETs); production of reactive oxygen and nitrogen species (e.g., H₂O₂ and nitric oxide); and modulation of immune cell infiltration and function within the tumor microenvironment. During metastasis, neutrophils facilitate cancer dissemination through three principal mechanisms: (1) promoting epithelial–mesenchymal transition (EMT) via inflammatory signaling, adhesion molecule interactions, and lipid metabolic support; (2) establishing pre-metastatic niches by remodeling distant organ stroma through NETs and matrix metalloproteinases; and (3) reactivating dormant tumor cells in response to chronic inflammation, viral infection, or stress hormones. Collectively, neutrophils function as central regulators across all stages of tumor evolution, influencing cancer growth, immune evasion, and metastatic progression. This review aims to provide a comprehensive synthesis of neutrophil-mediated mechanisms in the tumor microenvironment and highlight emerging strategies for neutrophil-targeted cancer therapy. Full article

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients. Full article

Background: The persistence of chemotherapy-resistant and dormant cancer cells remains a critical challenge in the treatment of lung cancer. Objectives: This review focuses on non-small cell lung cancer and small cell lung cancer, examining the complex mechanisms that drive treatment resistance. Methods: This review analyzed current studies on chemotherapy resistance in NSCLC and SCLC, focusing on tumor microenvironment, genetic mutations, cancer cell heterogeneity, and emerging therapies. Results: Conventional chemotherapy and targeted therapies, such as tyrosine kinase inhibitors, often fail due to factors including the tumor microenvironment, genetic mutations, and cancer cell heterogeneity. Dormant cancer cells, which can remain undetected in a quiescent state for extended periods, pose a significant risk of recurrence upon reactivation. These cells, along with intrinsic resistance mechanisms, greatly complicate treatment efforts. Understanding these pathways is crucial for the development of more effective therapies. Emerging strategies, including combination therapies that target multiple pathways, are under investigation to improve treatment outcomes. Innovative approaches, such as antibody–drug conjugates and targeted protein degradation, offer promising solutions by directly delivering cytotoxic agents to cancer cells or degrading proteins that are essential for cancer survival. The lung cancer organoid model shows substantial promise to advance both research and clinical applications in this field, enhancing the ability to study resistance mechanisms and develop personalized treatments. The integration of current research underscores the need for continuous innovation in treatment modalities. Conclusions: Personalized strategies that combine novel therapies with an in-depth understanding of tumor biology are essential to overcome the challenges posed by treatment-resistant and dormant cancer cells in lung cancer. A multifaceted approach has the potential to significantly improve patient outcomes. Full article

Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse. Full article

Background: Ewing sarcoma is a rare tumor of the bone or soft tissues characterized by diffuse membranous staining for CD99. As this tumor remains incurable in the metastatic, relapsed, and refractory settings, we explored the downstream immune implications of targeting CD99. Methods: We discovered a human anti-CD99 antibody (NOA2) by phagemid panning and investigated NOA2 immune cell-mediated cytotoxicity in vitro and in vivo focusing on the myeloid cell compartment, given that M2 macrophages are present in human tumors and associated with a poor prognosis. Results: NOA2 is capable of inducing immune effector cell-mediated Ewing death in vitro via engagement of macrophages. Mice with metastatic Ewing tumors, treated with NOA2, experience tumor growth arrest and an associated increase in intratumoral macrophages. Further, incubation of macrophages and Ewing cells with NOA2, in conjunction with anti-PILRα antibody blockade in vitro, results in the reactivation of previously dormant macrophages possibly due to interrupted binding of Ewing CD99 to macrophage PILRα. Conclusions: These studies are the first to demonstrate the role of human immune effector cells in anti-CD99-mediated Ewing tumor death. We propose that the engagement of CD99 by NOA2 results in the recruitment of intratumoral macrophages. In addition, interruption of the CD99:PILRα checkpoint axis may be a relevant therapeutic approach to activate tumor-associated macrophages. Full article

While endocrine therapy remains the mainstay of treatment for ER-positive, HER2-negative breast cancer, tumor progression and disease recurrence limit the utility of current standards of care. While existing therapies may allow for a prolonged progression-free survival, however, the growth-arrested (essentially dormant) state of residual tumor cells is not permanent and is frequently a precursor to disease relapse. Tumor cells that escape dormancy and regain proliferative capacity also tend to acquire resistance to further therapies. The cellular process of autophagy has been implicated in the adaptation, survival, and reactivation of dormant cells. Autophagy is a cellular stress mechanism induced to maintain cellular homeostasis. Tumor cells often undergo therapy-induced autophagy which, in most contexts, is cytoprotective in function; however, depending on how the autophagy is regulated, it can also be non-protective, cytostatic, or cytotoxic. In this review, we explore the literature on the relationship(s) between endocrine therapies and autophagy. Moreover, we address the different functional roles of autophagy in response to these treatments, exploring the possibility of targeting autophagy as an adjuvant therapeutic modality together with endocrine therapies. Full article

Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors. Full article

Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers. Full article

Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells. Full article

One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL) in the adjuvant setting may reduce the persistence of disseminated tumor cells and thereby might improve outcome, specifically in a population of patients with a low estrogen microenvironment. More recently, the results of a large meta-analysis from 41 randomized trials comparing a bisphosphonate (BP) to placebo or to an open control have been presented at the 2013 San Antonio Breast Cancer Meeting. Data on 17,016 patients confirm that adjuvant BPs, irrespective of the type of treatment or the treatment schedule and formulation (oral or intra-venously (IV)), significantly reduced bone recurrences and improved breast cancer survival in postmenopausal women. No advantage was seen in premenopausal women. BPs are soon likely to become integrated into standard practice. Published data on the mechanisms involved in tumor cell seeding from the primary site, in homing to bone tissues and in the reactivation of dormant tumor cells will be reviewed; these might offer new ideas for innovative combination strategies. Full article