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Annual Review of Pathology Jan 2023Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.
Topics: Humans; Drug Resistance, Neoplasm; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal
PubMed: 36130070
DOI: 10.1146/annurev-pathmechdis-031621-024600 -
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 -
Annual Review of Physiology Feb 2020Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the... (Review)
Review
Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
Topics: Acids; Animals; Humans; Hydrogen-Ion Concentration; Neoplasm Metastasis; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 31730395
DOI: 10.1146/annurev-physiol-021119-034627 -
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 -
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 -
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 -
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