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Cell Mar 2011The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle... (Review)
Review
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
Topics: Animals; Genomic Instability; Humans; Neoplasm Invasiveness; Neoplasms; Signal Transduction; Stromal Cells
PubMed: 21376230
DOI: 10.1016/j.cell.2011.02.013 -
Nature Medicine Nov 2013Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the... (Review)
Review
Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Topics: Cell Cycle Checkpoints; Disease Progression; Humans; Immunotherapy; Inflammation; Macrophages; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Tumor Microenvironment
PubMed: 24202395
DOI: 10.1038/nm.3394 -
Signal Transduction and Targeted Therapy Mar 2020Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of... (Review)
Review
Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
Topics: Epigenesis, Genetic; Humans; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 32296047
DOI: 10.1038/s41392-020-0134-x -
Cell Oct 2011Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to... (Review)
Review
Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting.
Topics: Animals; Basement Membrane; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Prognosis; Signal Transduction; Stromal Cells
PubMed: 22000009
DOI: 10.1016/j.cell.2011.09.024 -
Cancer Cell Mar 2012Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of... (Review)
Review
Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.
Topics: Cell Movement; Cell Proliferation; Humans; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Signal Transduction; Stromal Cells; Tumor Microenvironment
PubMed: 22439926
DOI: 10.1016/j.ccr.2012.02.022 -
Cancer Research Jun 2019Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as... (Review)
Review
Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as interactions between cancer cells and multiple microenvironments. The outcome is the development of a nearby or distant discontiguous secondary mass. To successfully disseminate, metastatic cells acquire properties in addition to those necessary to become neoplastic. Heterogeneity in mechanisms involved, routes of dissemination, redundancy of molecular pathways that can be utilized, and the ability to piggyback on the actions of surrounding stromal cells makes defining the hallmarks of metastasis extraordinarily challenging. Nonetheless, this review identifies four distinguishing features that are required: motility and invasion, ability to modulate the secondary site or local microenvironments, plasticity, and ability to colonize secondary tissues. By defining these first principles of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.
Topics: Animals; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Tumor Microenvironment
PubMed: 31053634
DOI: 10.1158/0008-5472.CAN-19-0458 -
Journal of Hematology & Oncology Jan 2021Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs harbor gain of function mutations in... (Review)
Review
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs harbor gain of function mutations in either KIT or PDGFRα. Determination of the GIST molecular subtype upon diagnosis is important because this information informs therapeutic decisions in both the adjuvant and metastatic setting. The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first line treatment for metastatic GIST. However, despite a clinical benefit rate of 80%, the majority of patients with GIST experience disease progression after 2-3 years of imatinib therapy. Second and third line options include sunitinib and regorafenib, respectively, and yield low response rates and limited clinical benefit. There have been recent FDA approvals for GIST including ripretinib in the fourth-line setting and avapritinib for PDGFRA exon 18-mutant GIST. This article aims to review the optimal treatment approach for the management of patients with advanced GIST. It examines the standard treatment options available but also explores the novel treatment approaches in the setting of imatinib refractory GIST.
Topics: Animals; Antineoplastic Agents; Disease Management; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Neoplasm Metastasis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sunitinib
PubMed: 33402214
DOI: 10.1186/s13045-020-01026-6 -
Molecular Cell Jul 2019Bulk genomic analyses and expression profiling of clinical specimens have shaped much of our understanding of cancer in patients. However, human tumors are intricate... (Review)
Review
Bulk genomic analyses and expression profiling of clinical specimens have shaped much of our understanding of cancer in patients. However, human tumors are intricate ecosystems composed of diverse cells, including malignant, immune, and stromal subsets, whose precise characterization is masked by bulk genomic methods. Single-cell genomic techniques have emerged as powerful approaches to dissect human tumors at the resolution of individual cells, providing a compelling approach to deciphering cancer biology. Here, we discuss some of the common themes emerging from initial studies of single-cell RNA sequencing in cancer and then highlight challenges in cancer biology for which emerging single-cell genomics methods may provide a compelling approach.
Topics: Antineoplastic Agents; Cell Communication; Cell Line, Tumor; Cell Lineage; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Neoplasms; Neoplastic Cells, Circulating; RNA, Neoplasm; Single-Cell Analysis
PubMed: 31299208
DOI: 10.1016/j.molcel.2019.05.003 -
Annals of Surgical Oncology Oct 2020Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Complete resection is the only potentially curative... (Review)
Review
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Complete resection is the only potentially curative treatment, although recurrence is common, occurring in approximately 40-50% of patients. The introduction of effective molecularly targeted therapies for GISTs has dramatically changed the clinical management paradigms for, and prognosis of, patients with intermediate- and high-risk GISTs, as well as those with locally advanced and metastatic disease. In this article, we review landmark studies that evaluated the use and efficacy of the tyrosine kinase inhibitors imatinib and sunitinib in the adjuvant and neoadjuvant settings for resectable primary and limited resectable metastatic GISTs.
Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Recurrence, Local
PubMed: 32734368
DOI: 10.1245/s10434-020-08869-w -
Molecular Cancer Mar 2019The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current... (Review)
Review
The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.
Topics: Animals; Antineoplastic Agents; Cell Communication; Drug Resistance, Neoplasm; Extracellular Vesicles; Humans; Neoplasms; Tumor Microenvironment
PubMed: 30925923
DOI: 10.1186/s12943-019-0965-7