-
Cancer Cell Nov 2016Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic... (Review)
Review
Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic niche can be primed and established through a complex interplay among primary tumor-derived factors, tumor-mobilized bone marrow-derived cells, and local stromal components. We review here our current understanding of the key components and underlying mechanisms for pre-metastatic niche formation. We propose six characteristics that define the pre-metastatic niche, which enable tumor cell colonization and promote metastasis, including immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. We highlight the significance of the pre-metastatic niche, and discuss potential implications and future research directions.
Topics: Bone Marrow Cells; Cellular Reprogramming; Disease Progression; Humans; Immune Tolerance; Neoplasm Metastasis; Neoplasms; Stromal Cells; Tumor Microenvironment
PubMed: 27846389
DOI: 10.1016/j.ccell.2016.09.011 -
Cancer Cell Dec 2016Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant... (Review)
Review
Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.
Topics: Biomarkers, Tumor; Cell Communication; Exosomes; Extracellular Vesicles; Humans; Neoplasm Metastasis; Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 27960084
DOI: 10.1016/j.ccell.2016.10.009 -
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 -
Pathologica Apr 2022Phyllodes tumors (PT) are fibroepithelial neoplasms of the breast showing a peculiar leaf-like appearance. They account for 0.3 to 1% of all primary breast tumors and... (Review)
Review
Phyllodes tumors (PT) are fibroepithelial neoplasms of the breast showing a peculiar leaf-like appearance. They account for 0.3 to 1% of all primary breast tumors and 2.5% of all fibroepithelial breast tumors. PT are classified into benign, borderline and malignant based upon their stromal morphology with a distribution of 60%, 20%, and 20%, respectively. Malignant PT of the breast constitute an uncommon challenging group of fibroepithelial neoplasms. They have a relatively high tendency to recur, although distant metastasis is uncommon, and nearly exclusive to malignant PT. Adequate surgical resection remains the standard approach to achieve maximal local control. Giant malignant PT are rare and a pose a diagnostic dilemma for pathologists, especially when comprised of sarcomatous elements. This review highlights the morphological features of PT detected in cytology and histology specimens and discusses diagnostic pitfalls and differential diagnosis.
Topics: Breast; Breast Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Neoplasms, Fibroepithelial; Phyllodes Tumor
PubMed: 35414723
DOI: 10.32074/1591-951X-754 -
Seminars in Cancer Biology Feb 2020Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor - glioblastoma and... (Review)
Review
Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor - glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%-45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs' microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.
Topics: Animals; Biomarkers; Brain Neoplasms; Disease Management; Disease Progression; Disease Susceptibility; Glioblastoma; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Stem Cell Niche; Stromal Cells; Tumor Microenvironment
PubMed: 31654711
DOI: 10.1016/j.semcancer.2019.10.010 -
Nature Reviews. Cancer Jul 2015Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological... (Review)
Review
Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.
Topics: Animals; Cell Hypoxia; Fibroblasts; Humans; Immune Tolerance; Neoplasm Recurrence, Local; Neoplasms; Radiation Tolerance; Transforming Growth Factor beta; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 26105538
DOI: 10.1038/nrc3958 -
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 -
Journal of Clinical Oncology : Official... Jan 2018GI stromal tumors (GISTs) are neoplasms with a varying malignancy potential ranging from virtually indolent tumors to rapidly progressing cancers. GISTs occur throughout... (Review)
Review
GI stromal tumors (GISTs) are neoplasms with a varying malignancy potential ranging from virtually indolent tumors to rapidly progressing cancers. GISTs occur throughout the intestinal tract, and most harbor an activating mutation in either KIT or platelet-derived growth factor A ( PDGFRA). Diagnosis is made using immunohistochemistry, but molecular testing with mutation analysis is paramount for selection of appropriate therapy. Most small GISTs are cured with surgery. Tyrosine kinase inhibitor (TKI) therapy has led to substantial improvements in survival, both for patients with localized GIST and those with advanced disease. Adjuvant therapy with imatinib benefits patients with a high risk of recurrence, with studies suggesting most benefit with at least 3 years of therapy. Neoadjuvant imatinib therapy should be considered for patients requiring extensive surgery, aiming at shrinking the tumor to allow organ preservation and less extensive surgery. The following three TKIs have been approved for the management of advanced disease: imatinib, sunitinib, and regorafenib; imatinib is usually the best tolerated of the three and the standard first-line treatment. TKIs benefit the majority of patients with advanced GIST but have no or limited efficacy in patients with the PDGFRA D842V mutation or patients with GIST lacking KIT and PDGFRA mutations. Surgery, the mainstay of primary tumor management, also plays a role in the advanced disease setting for selected patients, as do some other approaches such as palliative radiation therapy. Research continues to identify novel therapies, in particular effective agents to treat TKI-refractory disease.
Topics: Disease-Free Survival; Drug Resistance, Neoplasm; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Receptor, Platelet-Derived Growth Factor alpha
PubMed: 29220298
DOI: 10.1200/JCO.2017.74.9705 -
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