This volume will be the first to provide a comprehensive description of tumor dormancy. It will define the clinical and biological aspects of this phenomenon, as well as the cellular and molecular mechanisms associated with tumor dormancy. Chapters will be authored by world-renewed experts who are conducting cutting-edge research in the field. A unique feature will be a conclusive paragraph detailing future development and foreseeable clinical applications at the end of each chapter. The volume will serve as a fundamental instrument for every researcher and clinician interested in the field of tumor dormancy as well as a means of disseminating stimulating concepts and prompting the development of innovative technological solutions.
This third volume in the series Tumor Dormancy, Quiescence, and Senescence discusses the role of tumor dormancy and senescence in a number of diseases, including breast cancer, ovarian cancer and leukemia. The contents are organized under five subheadings: General Applications, Role in Breast Cancer, Role in Ovarian Cancer, Role in Leukemia and Role in Cardiovascular Disease. The first section includes basic information on the definition of dormancy, how cells become senescent and what they do, along with an appraisal of the current state of research on dormancy. Section Two explores dormancy in breast cancer, including the progression of hormone-dependent mammary tumors after dormancy. Section Three details the resistance of Type II ovarian tumors, in which the resistant tumor cell population persists after chemotherapy in a state of dormancy, with recurrent tumors arising upon transformation of such dormant cells back to malignant growth. This section explains how lineage, histological subtypes and grade influence the differential response of ovarian cancer resistance to platinum drugs. The fourth section explores leukemia, discussing regulation of the promyelocytic leukemia protein and its role in premature senescence. The final section explores the role of senescence and autophagy in age-related cardiovascular diseases and the observation that autophagy seems to retard cardiac senescence. Like the two preceding volumes in the series, Volume 3 stands out for its comprehensive approach, its roster of some 26 expert contributors representing seven different countries and its up-to-date review of leading-edge technology and methods.
In this second volume in the series exploring Tumor Dormancy, Quiescence, and Cellular Senescence, discussion is focused on the role of tumor dormancy in diseases such as breast cancer, melanoma, prostate cancer, liver cancer and lung cancer. M. A. Hayat, the series editor, writes in the preface that little is known of factors regulating the transition of residual cancer into a dormant state or the subsequent reinitiation of growth. A majority of us, he says, have in situ tumors that may remain dormant or may progress into a lethal form of cancer; the former are prevented from recruiting their own blood supply. Section I covers Molecular Mechanisms, with chapters on the role of NAE inhibitor MLN4924; oncogene-induced senescence; the role played by mitogen-activated protein kinase in the induction of cellular senescence; mechanisms of premature cell senescence and other topics. Section II examines Tumor and Cancer, discussing defects in chromatin structure and diseases; the role of fibrosis in tumor progression and the dormant to proliferative switch; the function of ING proteins in cancer and senescence and more. The final section is devoted to Stem Cells and Cancer Stem Cells, featuring chapters showing that senescent-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells; that the transcription factor Gata2 regulates quiescence in haematopoietic stem and progenitor cells; and discussing dormancy and recurrence of cancer stem cells in bone. The contributors point out that the quiescent state regulates hematopoietic stem cells and muscle stem cells, and detail the role of kinase in the mediation of reversible quiescent state in a subset of ovarian, pancreatic, and colon cancers. Molecular mechanisms underlying stress-induced cellular senescence and accumulation of reactive oxygen species and induction of premature senescence are also presented. Discussion includes the important role of microRNAs in oxidative stress-induced apoptosis and senescence and the effect of microRNA as a modulator of cell proliferation in lung cancer. The book includes an explanation of the suppression of cellular senescence in glioblastoma brain tumor. Taking a broad and varied perspective, this volume was written by 70 contributors representing 11 countries.
Cellular Immune Mechanisms and Tumor Dormancy features the work of internationally recognized experts from various disciplines as they discuss the phenomenon of tumor dormancy in humans. Animal models are described in which cellular and molecular components of the immune control of dormancy have been identified, and the relevance of these models to human cancer patients is recognized. Data derived from studies of organ transplantation, adjuvant chemotherapy, radiotherapy, anaesthesia, surgery, and whole blood transfusion is presented to show the vulnerability of cellular mechanisms maintaining dormancy. The potential for increasing the incidence of dormancy in micro metastases is also shown for non-small cell lung cancer, lymphoma, and leukemia. Cellular Immune Mechanisms and Tumor Dormancy is an important reference volume that will benefit researchers from many disciplines, including immunologists, pathologists, surgeons, and clinicians
Metastasis is the major cause of mortality in cancer patients. Metastases can be present at the time of diagnosis or can occur years or decades after the removal of the primary tumor and treatment. This long latency in the manifestation of recurrent metastatic disease is explained clinically by the persistence of quiescent tumor cells that disseminated early in the course of the disease from the primary tumor to select distant organs. These residing disseminated tumor cells (DTCs) at distant organs lay dormant and asymptomatic until reawakened to form overt metastases. Importantly, the quiescent nature of these “hibernating” DTCs facilitates their resistance to conventional therapies that target actively dividing tumor cells. Therefore, unraveling the biology of dormancy and reactivation of the residing DTCs to life-threatening lesions is of utmost importance in order to develop new therapeutic strategies to prevent the recurrent metastatic disease from ever emerging or to better treat these recurrent cancers. The mechanisms underlying the biology of tumor dormancy and their reactivation to overt metastases are just beginning to emerge thanks to a growing appreciation of the potentially chronic nature of some cancers and the development of experimental model systems for their study. In this Research Topic, we will follow the journey of circulating tumor cells (CTCs) dispatching from the primary site until their successful lodging into a new and foreign site to become DTCs. We will explore the intrinsic mechanisms along with microenvironmental cues and niches that they encounter during their journey that may dictate their fate.
Breast cancer recurrence is the primary cause of mortality in breast cancer, and although advances have been made in the treatment of primary breast cancer, recurrent breast cancer remains uncurable. Targeted therapy has had a major impact on survival across multiple cancer types, including breast cancer, however patients who respond to targeted therapy ultimately relapse. Residual disease, the tumor cells that survive initial therapy, represent an attractive therapeutic target, however little is known about the biology of these cells. We use mouse models of breast cancer to investigate the phenotype of residual disease that survives targeted therapy, and to explore approaches to inhibit tumor recurrence. Residual disease exhibits cellular dormancy in models driven by distinct oncogenic pathways. Gene expression profiling reveals that residual tumor cells are enriched for a phenotype associated with normal and neoplastic stem-like cells, but are not enriched for tumor initiative cells. Interventions that inhibit inflammatory signaling inhibit tumor recurrence, however increasing inflammation promotes tumor recurrence. Inflammatory macrophages may be leukocytes that promote inflammation and drive recurrence in these models. Together, our findings present a more comprehensive picture of residual tumor cells surviving targeted therapy, and suggest possible therapeutic strategies for targeting residual disease that gives rise to cancer recurrence.
This volume is based on the Workshop on Systems Biology of Tumor Dormancy meeting, held July 25th to July 28th, 2011. The first annual CCSB workshop brought together biologists, clinicians, mathematicians, and computer scientists to discuss various aspects of tumor dormancy and develop novel mathematical/computational models with the keynote speakers. Specific topics included the angiogenic switch, immune system interactions, cancer stem cells and signaling.
When breast tumor cells encounter stress due to cancer therapies, they may enter a dormant state, escaping from treatment-induced apoptosis. Dormant cells may eventually regain proliferative capabilities and cause recurrent metastatic disease, which is the leading cause of mortality in breast cancer patients. We sought to determine if a high dose of radiation therapy (RT) or combined chemo-immunotherapy, with and without the blockade of autophagy by chloroquine (CQ), could overcome treatment-induced tumor dormancy or relapse. We found that autophagy contributes in part to treatment-induced tumor dormancy. We also found that three therapeutic strategies were successful in inhibiting or preventing tumor relapse. These include: 18Gy/day RT, chemotherapy combined with the blockade of autophagy, and combined chemo-immunotherapy. Follow-up studies are needed to determine the feasibility of preventing tumor relapse by prolonging tumor dormancy versus eliminating dormant tumor cells.
This important book provides up-to-date information on a series of topical issues relating to the approach to minimal residual disease in breast cancer patients. It first explains how the study of minimal residual disease and circulating and disseminated tumor cells (CTCs/DTCs) can assist in the understanding of breast cancer metastasis. A series of chapters then discuss the various technologies available for the detection and characterization of CTCs and DTCs, pinpointing their merits and limitations. Detailed consideration is given to the relevance of CTCs and DTCs, and their detection, to clinical research and practice. The role of other blood-based biomarkers is also addressed, and the closing chapters debate the challenges facing drug and biomarker co-development and the use of CTCs for companion diagnostic development. This book will be of interest and assistance to all who are engaged in the modern management of breast cancer.
The successful treatment of breast cancer is limited due to a fraction of tumor cells escaping drug-treatment by entering a dormant state, only to relapse years or decades later at distant sites. Host-driven chronic inflammatory cells such as M2 macrophages play an important role in tumorigenesis, but the role of tumor-intrinsic inflammatory signaling involved in tumor dormancy and recurrence is unknown. We sought to determine the role of tumor-intrinsic inflammatory pathways in mouse mammary carcinoma cells (MMC) treated with Adriamycin (ADR), a clinically relevant chemotherapeutic drug. We found that ADR-induced dormant tumor cells autonomously produced pro-inflammatory cytokines, in vitro. MMC treated with Chloroquine (CQ) prior to ADR treatment displayed a delay in relapse, or prolonging of dormancy, when compared to ADR-treated MMC. Additional gene array data showed predicated activation of NF-[kappa]B p65 in ADR-treated dormant MMC that eventually relapsed. These data suggest that the anti-inflammatory function of CQ led to prolonged dormancy. To test this, we investigated the role of inflammatory signaling pathways directly by shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout of NF-[kappa]B p65 in MMC. We found that knockdown of NF-[kappa]B p65 resulted in fewer dormant cells after ADR treatment and reduced rate of relapse, in vitro. NF-[kappa]B p65 was also found to reduce the immunomodulatory effects of ADR, with shNF-[kappa]B p65 showing increased upregulation of neu upon ADR treatment. Additionally, we found NF-[kappa]B p65 to be associated with a higher infiltration of CD8+ T cells and anti-tumor T cell responses. Our findings suggest a dual role of tumor-intrinsic NF-[kappa]B p65 pathway, allowing for escape from drug treatment through dormancy which leads to relapse, but also for proper lymphocyte infiltration and subsequent anti-tumor activity.
