The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain topics of considerable controversy. Opinions about the validity of the ...CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.
Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, ...is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases.
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•Intrailiac artery injection allows studies of bone metastasis initiation•Bone micrometastases reside in the microenvironment niche with active osteogenesis•The niche cells boost tumor proliferation via adherens junctions (AJs)•The mTOR pathway lies downstream of AJs and mediates metastasis initiation
Wang et al. model breast cancer bone micrometastasis and identify an osteogenic niche that supports this process. Heterotypic adherens junctions form between cancer cells and stromal cells in these niches and activate mTOR to promote micrometastasis progression.
Breast cancer ecosystems are composed of complex cell types, including tumor, stromal and immune cells, each of which can assume diverse phenotypes. Both the heterogeneous composition and spatially ...distinct tumor microenvironment impact breast cancer progression, treatment response and therapeutic resistance. Thus, a deeper understanding of breast cancer heterogeneity may help facilitate the development of novel therapies and improve outcomes for patients. The advent of paradigm shifting single-cell analysis and spatial pathologies allows for a comprehensive analysis of the tumor ecosystem as well as the interactions between its components at unprecedented resolution. In this review, we discuss the insights gained through single-cell analysis and spatial pathologies on breast cancer heterogeneity.
Breast cancer is not a single disease, but is instead a collection of diseases that have distinct histopathological features, genetic and genomic variability, and diverse prognostic outcomes. Thus, ...no individual model would be expected to completely recapitulate this complex disease. Here, the models commonly used to investigate breast cancer including cell lines, xenografts and genetically engineered mice, are discussed to help address the question: what is the most powerful way to investigate this heterogeneous disease?
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Much effort has been devoted in the development of efficient catalysts for electrochemical reduction of CO2. Molecular level understanding of electrode-mediated process, particularly the role of ...bicarbonate in increasing CO2 reduction rates, is still lacking due to the difficulty of directly probing the electrochemical interface. We developed a protocol to observe normally invisible reaction intermediates with a surface enhanced spectroscopy by applying square-wave potential profiles. Further, we demonstrate that bicarbonate, through equilibrium exchange with dissolved CO2, rather than the supplied CO2, is the primary source of carbon in the CO formed at the Au electrode by a combination of in situ spectroscopic, isotopic labeling, and mass spectroscopic investigations. We propose that bicarbonate enhances the rate of CO production on Au by increasing the effective concentration of dissolved CO2 near the electrode surface through rapid equilibrium between bicarbonate and dissolved CO2.
Metastasis is the most devastating stage of cancer progression and causes the majority of cancer-related deaths. Clinical observations suggest that most cancers metastasize to specific organs, a ...process known as “organotropism.” Elucidating the underlying mechanisms may help identify targets and treatment strategies to benefit patients. This review summarizes recent findings on tumor-intrinsic properties and their interaction with unique features of host organs, which together determine organ-specific metastatic behaviors. Emerging insights related to the roles of metabolic changes, the immune landscapes of target organs, and variation in epithelial-mesenchymal transitions open avenues for future studies of metastasis organotropism.
Clinical observations suggest that most cancers metastasize to specific organs, a process known as “organotropism.” This Review from Gao et al. highlights recent findings on tumor-intrinsic properties and their interaction with unique cellular, architectural, metabolic, and immune features of host organs, which together determine organ-specific metastatic behaviors.
Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that ...define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for ...cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.
Mechanisms of cancer metastasis Castaneda, Maria; den Hollander, Petra; Kuburich, Nick A. ...
Seminars in cancer biology,
December 2022, 2022-12-00, 20221201, Letnik:
87
Journal Article
Recenzirano
Odprti dostop
Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires ...understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient’s mutation and/or immune profile are also highlighted.
Triple-negative breast cancers (TNBCs), which lack receptors for estrogen, progesterone, and amplification of epidermal growth factor receptor 2, are highly aggressive. Consequently, patients ...diagnosed with TNBCs have reduced overall and disease-free survival rates compared to patients with other subtypes of breast cancer. TNBCs are characterized by the presence of cancer cells with mesenchymal properties, indicating that the epithelial to mesenchymal transition (EMT) plays a major role in the progression of this disease. The EMT program has also been implicated in chemoresistance, tumor recurrence, and induction of cancer stem cell (CSC) properties. Currently, there are no targeted therapies for TNBC, and hence, it is critical to identify the novel targets to treat TNBC.
A library of compounds was screened for their ability to inhibit EMT in cells with mesenchymal phenotype as assessed using the previously described Z-cad reporters. Of the several drugs tested, GSK3β inhibitors were identified as EMT inhibitors. The effects of GSK3β inhibitors on the properties of TNBC cells with a mesenchymal phenotype were assessed using qRT-PCR, flow cytometry, western blot, mammosphere, and migration and cell viability assays. Publicly available datasets also were analyzed to examine if the expression of GSK3β correlates with the overall survival of breast cancer patients.
We identified a GSK3β inhibitor, BIO, in a drug screen as one of the most potent inhibitors of EMT. BIO and two other GSK3β inhibitors, TWS119 and LiCl, also decreased the expression of mesenchymal markers in several different cell lines with a mesenchymal phenotype. Further, inhibition of GSK3β reduced EMT-related migratory properties of cells with mesenchymal properties. To determine if GSK3β inhibitors target mesenchymal-like cells by affecting the CSC population, we employed mammosphere assays and profiled the stem cell-related cell surface marker CD44+/24- in cells after exposure to GSK3β inhibitors. We found that GSK3β inhibitors indeed decreased the CSC properties of cell types with mesenchymal properties. We treated cells with epithelial and mesenchymal properties with GSK3β inhibitors and found that GSK3β inhibitors selectively kill cells with mesenchymal attributes while sparing cells with epithelial properties. We analyzed patient data to identify genes predictive of poor clinical outcome that could serve as novel therapeutic targets for TNBC. The Wnt signaling pathway is critical to EMT, but among the various factors known to be involved in Wnt signaling, only the higher expression of GSK3β correlated with poorer overall patient survival.
Taken together, our data demonstrate that GSK3β is a potential target for TNBCs and suggest that GSK3β inhibitors could serve as selective inhibitors of EMT and CSC properties for the treatment of a subset of aggressive TNBC. GSK3β inhibitors should be tested for use in combination with standard-of-care drugs in preclinical TNBC models.
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