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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 -
Nature Reviews. Cancer Aug 2016Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are... (Review)
Review
Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.
Topics: Cell Differentiation; Cell Lineage; Cytokines; Disease Progression; Drug Resistance, Neoplasm; Epigenesis, Genetic; Extracellular Matrix; Fibroblasts; Fibrosis; Forecasting; Humans; Mesenchymal Stem Cells; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Tumor Microenvironment; Wound Healing
PubMed: 27550820
DOI: 10.1038/nrc.2016.73 -
International Journal of Gynaecology... Oct 2018Uterine sarcomas account for approximately 3%-7% of all uterine cancers. Since carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas remain...
Uterine sarcomas account for approximately 3%-7% of all uterine cancers. Since carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common subtype. Exclusion of several histologic variants of leiomyoma, as well as atypical smooth muscle tumors (so-called "smooth muscle tumors of uncertain malignant potential"), has highlighted that the vast majority of leiomyosarcomas are high-grade tumors associated with poor prognosis even when apparently confined to the uterus. Low-grade endometrial stromal sarcomas are indolent tumors associated with long-term survival. High-grade endometrial stromal sarcomas and undifferentiated endometrial sarcomas behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. The prognosis for carcinosarcomas (which are considered here in a postscript fashion) is usually worse than that for grade 3 endometrial carcinomas. Tumor stage is the single most important prognostic factor for uterine sarcomas.
Topics: Adenosarcoma; Carcinosarcoma; Female; Humans; Leiomyoma; Leiomyosarcoma; Neoplasm Grading; Neoplasm Staging; Prognosis; Sarcoma; Sarcoma, Endometrial Stromal; Smooth Muscle Tumor; Uterine Neoplasms
PubMed: 30306577
DOI: 10.1002/ijgo.12613 -
Cancer Chemotherapy and Pharmacology Feb 2021Breast cancer is presently the most predominant tumor type and the second leading cause of tumor-related deaths among women. Although advancements in diagnosis and... (Review)
Review
Breast cancer is presently the most predominant tumor type and the second leading cause of tumor-related deaths among women. Although advancements in diagnosis and therapeutics have momentously improved, chemoresistance remains an important challenge. Tumors oppose chemotherapeutic agents through a variety of mechanisms, with studies revealing that the tumor microenvironment (TME) is central to this process. The components of TME including stromal cells, immune cells, and non-stromal factors on exposure to chemotherapy promote the acquisition of resistant phenotype. Consequently, limited targeting of tumor cells leads to tumor recurrence after chemotherapy. Here, in this article, we summarize how TME alters chemotherapy responses in breast cancer. Furthermore, the role of different stromal cells viz., CAFs, TAMs, MSCs, endothelial cells, and cancer stem cells (CSC) in breast cancer chemoresistance is discussed in greater detail.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 33420940
DOI: 10.1007/s00280-020-04222-w -
Nature Reviews. Disease Primers Mar 2021Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 10 individuals per year in most countries. Around 80% of GIST have varying molecular changes,... (Review)
Review
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 10 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Naphthyridines; Neoplasm Recurrence, Local; Urea
PubMed: 33737510
DOI: 10.1038/s41572-021-00254-5 -
Current Opinion in Gastroenterology Nov 2019The purpose of this review is to review the past year's literature to provide comprehensive information to researchers, physicians, and the general public regarding the... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to review the past year's literature to provide comprehensive information to researchers, physicians, and the general public regarding the epidemiology, diagnosis, and treatment of gastrointestinal stromal tumors (GISTs). Common ground as well as divergent viewpoints will be highlighted and discussed.
RECENT FINDINGS
The diagnosis of GISTs may involve imaging tests such as computed tomorgraphy scan and MRI, endoscopy with or without endoscopic ultrasound, and biopsy. Only biopsy, however, can yield a positive diagnosis. As most GISTs express KIT protein, immunostaining for KIT and/or molecular genetic testing for mutations in KIT can diagnose 95% of GISTs. Regorafenib, a drug that inhibits various protein genes that lead to GIST development is a relatively new treatment modality.
SUMMARY
The current review should enable clinicians to best select the diagnostic and treatment approaches to GIST.
Topics: Biopsy, Needle; Combined Modality Therapy; Disease-Free Survival; Early Detection of Cancer; Female; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Male; Neoplasm Invasiveness; Neoplasm Staging; Phenylurea Compounds; Pyridines; Risk Assessment; Survival Analysis
PubMed: 31577561
DOI: 10.1097/MOG.0000000000000584 -
Trends in Cancer Jul 2022The view of cancer as a tumor cell-centric disease is now replaced by our understanding of the interconnection and dependency of tumor stroma. Cancer-associated... (Review)
Review
The view of cancer as a tumor cell-centric disease is now replaced by our understanding of the interconnection and dependency of tumor stroma. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the tumor microenvironment (TME), are involved in anticancer therapeutic resistance. As we unearth more solid evidence on the link between CAFs and tumor progression, we gain insight into the role of CAFs in establishing resistance to cancer therapies. Herein, we review the origin, heterogeneity, and function of CAFs, with a focus on how CAF subsets can be used as biomarkers and can contribute to therapeutic resistance in cancer. We also depict current breakthroughs in targeting CAFs to overcome anticancer therapeutic resistance and discuss emerging CAF-targeting modalities.
Topics: Cancer-Associated Fibroblasts; Drug Resistance, Neoplasm; Humans; Neoplasms; Stromal Cells; Tumor Microenvironment
PubMed: 35331673
DOI: 10.1016/j.trecan.2022.03.001 -
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