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Theranostics 2020: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca)-mediated...
: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca entry (SOCE) is the major route of Ca influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC metabolic reprogramming is unclear. : The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate and lung metastasis . Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. : STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, , from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. : Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis reprogramming HCC metabolism.
Topics: Animals; Anoikis; Calcium; Calcium Signaling; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Energy Metabolism; Humans; Liver Neoplasms; Mice; Neoplasm Metastasis; Neoplasm Proteins; Snail Family Transcription Factors; Stromal Interaction Molecule 1
PubMed: 32483465
DOI: 10.7150/thno.44025 -
Gastric Cancer : Official Journal of... May 2023Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of... (Review)
Review
Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody-drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.
Topics: Humans; Gastrointestinal Stromal Tumors; Imatinib Mesylate; Gastrointestinal Neoplasms; Stomach Neoplasms; Neoplasm Recurrence, Local; Antineoplastic Agents; Protein Kinase Inhibitors
PubMed: 36913072
DOI: 10.1007/s10120-023-01381-6 -
Molecular and Cellular Biochemistry Jun 2021The regulation of aromatase, an enzyme involved in the biosynthesis of estrogen in normal and cancer cells, has been associated with growth factor signaling and immune... (Review)
Review
The regulation of aromatase, an enzyme involved in the biosynthesis of estrogen in normal and cancer cells, has been associated with growth factor signaling and immune response modulation. The tissue-specific regulatory roles of these factors are of particular importance as local aromatase expression is strongly linked to cancer development/progression and disease outcomes in patients. Therefore, aromatase has become a chemotherapeutic target and aromatase inhibitors (AIs) are used in the clinic for treating hormone-dependent cancers. Although AIs have shown promising results in the treatment of cancers, the emerging increase in AI-resistance necessitates the development of new and improved targeted therapies. This review discusses the role of tumor and stromal-derived growth factors and immune cell modulators in regulating aromatase. Current single-agent and combination therapies with or without AIs targeting growth factors and immune checkpoints are also discussed. This review highlights recent studies that show new connections between growth factors, mediators of immune response, and aromatase regulation.
Topics: Animals; Aromatase; Aromatase Inhibitors; Humans; Neoplasm Proteins; Neoplasms
PubMed: 33599895
DOI: 10.1007/s11010-021-04099-0 -
Journal of Endocrinological... Jun 2023The pituitary tumour microenvironment encompasses a spectrum of non-tumoural cells, such as immune, stromal or endothelial cells, as well as enzymes and signalling... (Review)
Review
The pituitary tumour microenvironment encompasses a spectrum of non-tumoural cells, such as immune, stromal or endothelial cells, as well as enzymes and signalling peptides like cytokines, chemokines and growth factors, which surround the tumour cells and may influence pituitary tumour behaviour and tumourigenic mechanisms. Recently, there has been intensive research activity in this field describing various pituitary tumour-infiltrating immune and stromal cell subpopulations, and immune- and microenvironment-related pathways. Key changes in oncological therapeutic avenues resulted in the recognition of pituitary as a target of adverse events for patients treated with immune checkpoint regulators. However, these phenomena can be turned into therapeutic advantage in severe cases of pituitary tumours. Therefore, unravelling the pituitary tumour microenvironment will allow a better understanding of the biology and behaviour of pituitary tumours and may provide further developments in terms of diagnosis and management of patients with aggressively growing or recurrent pituitary tumours.
Topics: Humans; Pituitary Neoplasms; Tumor Microenvironment; Endothelial Cells; Neoplasm Recurrence, Local; Cytokines
PubMed: 37060402
DOI: 10.1007/s40618-023-02089-1 -
Histology and Histopathology Aug 2023Phyllodes tumor (PT) is a relatively rare breast tumor, accounting for <1% of all breast tumors. (Review)
Review
BACKGROUND
Phyllodes tumor (PT) is a relatively rare breast tumor, accounting for <1% of all breast tumors.
MAIN BODY
Adjuvant therapy with chemotherapy or radiation therapy, other than surgical excision, has not been established yet. PT, similar to other breast tumors, is classified as benign, borderline, and malignant according to the World Health Organization classification system, depending on stromal cellularity, stromal atypia, mitotic activity, stromal overgrowth, and tumor border. However, this histological grading system cannot effectively or fully reflect the clinical prognosis of PT. Several studies have investigated prognostic factors for PT as some PTs recur or metastasize to distant sites, and thus, prediction of prognosis is clinically imperative.
CONCLUSION
This review discusses clinicopathological factors, immunohistochemical markers, and molecular factors that have been investigated in previous studies to have an impact on the clinical prognosis of PT.
Topics: Humans; Female; Phyllodes Tumor; Prognosis; Neoplasm Recurrence, Local; Stromal Cells; Breast Neoplasms; Retrospective Studies
PubMed: 36866915
DOI: 10.14670/HH-18-600 -
Advances in Experimental Medicine and... 2021Phyllodes tumors of breast (PTB) have been known to an uncommon and particular disease to handle owing to diagnostic ambiguity and unpredictable clinical outcome....
Phyllodes tumors of breast (PTB) have been known to an uncommon and particular disease to handle owing to diagnostic ambiguity and unpredictable clinical outcome. Malignant phyllodes tumors (MPT) are diagnosed when there are marked stromal hypercellularity, atypia, increased mitoses of ≥10/10 HPFs, permeative tumor borders, and stromal overgrowth. The presence of a malignant heterologous element (MHE) places the tumor into the malignant category regardless of other histological features. Excision with negative margins should be achieved for recurrent and malignant phyllodes tumor. An ideal margin width remains to be determined, and may need to be considered in relation to factors such as tumor size and cosmesis. Without the convincing evidence of survival benefit, adjuvant RT has revealed more favorable local control rate compared with observation group. Stromal expression of Twist and Foxc2, epithelial-mesenchymal transition marker, was associated with high tumor grade and poor prognosis. Tumor-associated macrophage drives myoblast differentiation and malignant progression of PTB through a CCL18-driven signaling cascade amenable to antibody disruption. Recent targeted sequencing on PTBs provided insights into the molecular pathogenesis and genetic characterization with potential clinical implications.
Topics: Breast Neoplasms; Cell Differentiation; Epithelial-Mesenchymal Transition; Humans; Neoplasm Recurrence, Local; Phyllodes Tumor
PubMed: 33983602
DOI: 10.1007/978-981-32-9620-6_32 -
Matrix Biology : Journal of the... Sep 2020It is well accepted that the tumor microenvironment plays a pivotal role in cancer onset, development, and progression. The majority of clinical interventions are... (Review)
Review
It is well accepted that the tumor microenvironment plays a pivotal role in cancer onset, development, and progression. The majority of clinical interventions are designed to target either cancer or stroma cells. These emphases have been directed by one of two prevailing theories in the field, the Somatic Mutation Theory and the Tissue Organization Field Theory, which represent two seemingly opposing concepts. This review proposes that the two theories are mutually inclusive and should be concurrently considered for cancer treatments. Specifically, this review discusses the dynamic and reciprocal processes between stromal cells and extracellular matrices, using pancreatic cancer as an example, to demonstrate the inclusivity of the theories. Furthermore, this review highlights the functions of cancer associated fibroblasts, which represent the major stromal cell type, as important mediators of the known cancer hallmarks that the two theories attempt to explain.
Topics: Cancer-Associated Fibroblasts; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Lineage; Cytokines; Disease Progression; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasm Proteins; Neovascularization, Pathologic; Pancreatic Neoplasms; Signal Transduction; Stromal Cells; Tumor Microenvironment
PubMed: 32450219
DOI: 10.1016/j.matbio.2020.05.004 -
Cancer Research Oct 2022Epithelial transformation and carcinogenesis are characterized by profound alterations in cell mechanics that significantly affect multiple steps of the metastatic...
Epithelial transformation and carcinogenesis are characterized by profound alterations in cell mechanics that significantly affect multiple steps of the metastatic cascade. The ability of cancer cells to grow in the primary tumor, to locally invade through the confining extracellular matrix, to survive in circulation, and to extravasate into distant vital organs all depend on specific mechanical characteristics. Importantly, recent studies have shown that the mechanical properties of cancer cells also influence their interactions with immune and stromal cells. Here, we discuss the mechanical changes that cancer cells undergo during metastasis, how these changes affect immune and stromal responses, and the implications of these new insights for therapeutic intervention.
Topics: Extracellular Matrix; Humans; Neoplasm Metastasis; Neoplasms; Stromal Cells
PubMed: 35877197
DOI: 10.1158/0008-5472.CAN-22-0419 -
Best Practice & Research. Clinical... Jan 2022Non-epithelial cancers arising from the ovary are uncommon malignancies. Germ cell tumors of the ovary arise from primordial germ cells, and sex cord-stromal tumors of... (Review)
Review
Non-epithelial cancers arising from the ovary are uncommon malignancies. Germ cell tumors of the ovary arise from primordial germ cells, and sex cord-stromal tumors of the ovary represent a cluster of tumors arising from the sex cord and stromal compartment. Most patients diagnosed with germ cell tumors are young adults and adolescent females. In contrast, ovarian sex cord-stromal tumors more commonly occur in a mature age group. Advances in the adjuvant management of non-epithelial ovarian cancer following optimal surgical and pathological staging have improved patient survival outcomes. In addition, active surveillance is preferentially assigned to patients diagnosed with stage I germ cell tumor, stage 1A grade 1 immature teratoma, stage 1A yolk sac tumor, and stage 1AI sex cord-stromal tumors. This article discusses the importance of selecting the adjuvant treatment approach most suitable to the patients' surgical and pathological stages, thereby safeguarding patient outcomes.
Topics: Adolescent; Female; Humans; Neoplasm Staging; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Sex Cord-Gonadal Stromal Tumors
PubMed: 34493450
DOI: 10.1016/j.bpobgyn.2021.06.001 -
Frontiers in Immunology 2020The thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine originally cloned from a murine thymic stromal cell line, and subsequently a human homolog was... (Review)
Review
The thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine originally cloned from a murine thymic stromal cell line, and subsequently a human homolog was identified using database search methods. Human TSLP is mostly expressed in epithelial cells, among which are keratinocytes as well as stromal cells such as fibroblasts and immune cells. Human TSLP was first described to activate myeloid dendritic cells, which prime naïve T helper cells to produce high concentrations of Th2 cytokines, thus representing a key cytokine in triggering dendritic cells-mediated allergic Th2 inflammation. TSLP and/or its receptor has been shown to be expressed in several tumor types, where TSLP expression is associated with functional activities that can be associated or not with the induction of a Th2-prone tumor microenvironment, i.e., Th2-dependent and Th2-independent mechanisms. These mechanisms involve tissue- and immune cell target-dependent tumor-promoting or tumor-suppressive functions in different or even the same tumor type. Here we report and discuss the Th2-dependent and Th2-independent roles of TSLP in cancer and possible therapeutic targeting.
Topics: Animals; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neoplasms; Th2 Cells; Thymic Stromal Lymphopoietin
PubMed: 33042121
DOI: 10.3389/fimmu.2020.02088