The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be ...controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, ...which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets.
In this perspective, Plaks et al. focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, they also examine the prospects of targeting the niche components as preferable therapeutic targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ...ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.
Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix ...metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of ...macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.
Circulating Tumor Cells Plaks, Vicki; Koopman, Charlotte D.; Werb, Zena
Science (American Association for the Advancement of Science),
09/2013, Volume:
341, Issue:
6151
Journal Article
Peer reviewed
Open access
Much remains to be learned about CTCs and their clinical potential as biomarkers and therapeutic targets.
The major cause of cancer-associated mortality is tumor metastasis, but our understanding of ...this process is far from complete. During successful dissemination, tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, translocate to distant tissues, extravasate, adapt to the new microenvironment, and eventually seed, proliferate, and colonize to form metastases. Because dissemination mostly occurs through the blood, circulating tumor cells (CTCs) that have been shed into the vasculature and may be on their way to potential metastatic sites are of obvious interest (
1
). Here we discuss what is known about CTCs, and suggest future research directions that may help realize their clinical potential.
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Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling ...interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Since Gross and Lapiere firstly discovered matrix metalloproteinases (MMPs) as important collagenolytic enzymes during amphibian tadpole morphogenesis in 1962, this intriguing family of extracellular ...proteinases has been implicated in various processes of developmental biology. However, the pathogenic roles of MMPs in human diseases such as cancer have also garnered widespread attention. The most straightforward explanation for their role in cancer is that MMPs, through extracellular matrix degradation, pave the way for tumor cell invasion and metastasis. While this notion may be true for many circumstances, we now know that, depending on the context, MMPs may employ additional modes of functionality. Here, we will give an update on the function of MMPs in development and cancer, which may directly regulate signaling pathways that control tissue homeostasis and may even work in a non-proteolytic manner. These novel findings about the functionality of MMPs have important implications for MMP inhibitor design and may allow us to revisit MMPs as drug targets in the context of cancer and other diseases.
•MMPs are potent modulators of the microenvironment during development and cancer.•Recent findings indicate that MMPs can rearrange on the composition of adult stem cell niches.•MMPs can also directly regulate signaling pathways that control stem cell differentiation, expansion or apoptosis.•In this context, MMPs may function in a non-proteolytic manner via their hemopexin domain.•These novel aspects about the functionality of MMPs may allow us to reconsider their role as drug targets in cancer therapy.
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Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We ...developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.
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•Molecularly distinct tumor cells lead collective invasion in breast cancer•Keratin-14+ cells lead collective invasion across major subtypes of breast cancer•Invasive leader cells are generated by induction of a basal epithelial program•Basal epithelial gene expression is required for collective invasion
Collective invasion in breast cancer is led by specialized cancer cells defined by their expression of basal epithelial genes. Targeting the basal epithelial program is sufficient to disrupt the invasive process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • The outcome of the innate immune system is determined by the tumor context. • The balance of innate immune cells dictates the fate of cancer development. • Innate lymphoid cells are ...important in regulating tumorigenesis. • There is an emerging role for neutrophil subsets in tumor progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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