scholarly journals Competition and niche construction in a model of cancer metastasis

2017 ◽  
Author(s):  
Jimmy J. Qian ◽  
Erol Akçay
Keyword(s):  
Mathematical Model ◽  
Natural Selection ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Niche Construction ◽  
Primary Tumors ◽  
Darwinian Selection ◽  
Potential Explanation ◽  
The Cost

AbstractNiche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors.

scholarly journals Nanotechnology-Assisted Isolation and Analysis of Circulating Tumor Cells on Microfluidic Devices

Micromachines ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 774 ◽  
Author(s):  
Jie Cheng ◽  
Yang Liu ◽  
Yang Zhao ◽  
Lina Zhang ◽  
Lingqian Zhang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Liquid Biopsy ◽  
Cancer Metastasis ◽  
Human Peripheral Blood ◽  
Microfluidic Devices ◽  
Detection Sensitivity ◽  
Cell Capture ◽  
Primary Tumors ◽  
Downstream Analysis

Circulating tumor cells (CTCs), a type of cancer cell that spreads from primary tumors into human peripheral blood and are considered as a new biomarker of cancer liquid biopsy. It provides the direction for understanding the biology of cancer metastasis and progression. Isolation and analysis of CTCs offer the possibility for early cancer detection and dynamic prognosis monitoring. The extremely low quantity and high heterogeneity of CTCs are the major challenges for the application of CTCs in liquid biopsy. There have been significant research endeavors to develop efficient and reliable approaches to CTC isolation and analysis in the past few decades. With the advancement of microfabrication and nanomaterials, a variety of approaches have now emerged for CTC isolation and analysis on microfluidic platforms combined with nanotechnology. These new approaches show advantages in terms of cell capture efficiency, purity, detection sensitivity and specificity. This review focuses on recent progress in the field of nanotechnology-assisted microfluidics for CTC isolation and detection. Firstly, CTC isolation approaches using nanomaterial-based microfluidic devices are summarized and discussed. The different strategies for CTC release from the devices are specifically outlined. In addition, existing nanotechnology-assisted methods for CTC downstream analysis are summarized. Some perspectives are discussed on the challenges of current methods for CTC studies and promising research directions.

scholarly journals Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1539 ◽  
Author(s):  
Peter Ping Lin
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Mesenchymal Transition ◽  
Tumor Neovascularization ◽  
Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

scholarly journals Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Yun Li ◽  
Hua Liu ◽  
Jiahui Zhang ◽  
Jie Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Ovarian Cancer Cells ◽  
Skov3 Cell ◽  
Anoikis Resistance ◽  
Primary Tumors ◽  
Genome Wide

Abstract Background The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance. Methods Genome-wide CRISPR/Cas9 knockout screen was used to identify critical drivers of anoikis resistance using SKOV3 cell line and found protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) as a candidate. Quantitative real-time PCR (qRT-PCR) and immune-histochemistry (IHC) were used to measure differentially expressed PCMT1 in primary tissues and metastatic cancer tissues. PCMT1 knockdown/knockout and overexpression were performed to investigate the functional role of PCMT1 in vitro and in vivo. The expression and regulation of PCMT1 and integrin-FAK-Src pathway were evaluated using immunoprecipitation followed by mass spectrometry (IP-MS), western blot analysis and live cell imaging. Results We found that PCMT1 enhanced cell migration, adhesion, and spheroid formation in vitro. Interestingly, PCMT1 was released from ovarian cancer cells, and interacted with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer progression. Strikingly, treatment with an antibody against extracellular PCMT1 effectively reduced ovarian cancer cell invasion and adhesion. Our in vivo results indicated that overexpression of PCMT1 led to increased ascites formation and distant metastasis, whereas knockout of PCMT1 had the opposite effect. Importantly, PCMT1 was highly expressed in late-stage metastatic tumors compared to early-stage primary tumors. Conclusions Through systematically identifying the drivers of anoikis resistance, we uncovered the contribution of PCMT1 to focal adhesion (FA) dynamics as well as cancer metastasis. Our study suggested that PCMT1 has the potential to be a therapeutic target in metastatic ovarian cancer.

scholarly journals Breast Cancer Metastasis in the Skin with Hyperkeratotic Pigmentation Caused by Melanocyte Colonization

2018 ◽  
Vol 11 (3) ◽  
pp. 660-664
Author(s):  
Shino Ishihara-Yusa ◽  
Taku Fujimura ◽  
Chunbing Lyu ◽  
Masayuki Sugawara ◽  
Kazuhiro Sakamoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immunohistochemical Staining ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Rare Condition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Keratinocyte Proliferation

Pigmented breast cancer in the skin caused by nonneoplastic melanocytes of epidermal origin is a rare condition of metastasis from breast cancer, but the pathogenesis of this phenomenon is almost unknown. In this report, we describe a case of breast cancer metastasis in the skin with prominent hyperkeratotic pigmentation caused by nonneoplastic melanocyte colonization. Immunohistochemical staining revealed that the metastatic tumor cells produced IL-23, which is reported not only to induce IL-17 but also to inhibit cell apoptosis in breast cancer cells, which affects tumor progression. In addition to IL-23, substantial numbers of IL-17-producing cells were detected at the peritumoral area, suggesting that IL-17 might induce not only melanogenesis but also keratinocyte proliferation and tumorigenesis. Our report suggests possible mechanisms of hyperkeratotic pigmentation of breast cancer metastasis in the skin.

scholarly journals Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

2020 ◽  
Author(s):  
Junho Lee ◽  
Donggu Lee ◽  
Sean Lawler ◽  
Yangjin Kim
Keyword(s):  
Mathematical Model ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Tumor Invasion ◽  
Neutrophil Extracellular Traps ◽  
Tumor Cell Invasion ◽  
Invasion And Metastasis ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

AbstractLung cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by hijacking immune system for active growth and aggressive metastasis. Neutrophils, which in their original form should establish immune activities to the tumor as a first line of defense, are undermined by tumor cells to promote tumor invasion in several ways. In this study, we investigate the mutual interactions between the tumor cells and the neutrophils that facilitate tumor invasion by developing a mathematical model that involves taxis-reaction-diffusion equations for the critical components in the interaction. These include the densities of tumor and neutrophils, and the concentrations of signaling molecules and structure such as neutrophil extracellular traps (NETs). We apply the mathematical model to a Boyden invasion assay used in the experiments to demonstrate that the tumor-associated neutrophils can enhance tumor cell invasion by secreting the neutrophil elastase. We show that the model can both reproduce the major experimental observation on NET-mediated cancer invasion and make several important predictions to guide future experiments with the goal of the development of new anti-tumor strategies. Moreover, using this model, we investigate the fundamental mechanism of NET-mediated invasion of cancer cells and the impact of internal and external heterogeneity on the migration patterning of tumour cells and their response to different treatment schedules.Author summaryWhen cancer patients are diagnosed with tumours at a primary site, the cancer cells are often found in the blood or already metastasized to the secondary sites in other organs. These metastatic cancer cells are more resistant to major anti-cancer therapies, and lead to the low survival probability. Until recently, the role of neutrophils, specifically tumor-associated neutrophils as a member of complex tumor microenvironment, has been ignored for a long time due to technical difficulties in tumor biology but these neutrophils are emerging as an important player in regulation of tumor invasion and metastasis. The mutual interaction between a tumor and neutrophils from bone marrow or in blood induces the critical transition of the naive form, called the N1 type, to the more aggressive phenotype, called the N2 TANs, which then promotes tumor invasion. In this article, we investigate how stimulated neutrophils with different N1 and N2 landscapes shape the metastatic potential of the lung cancers. Our simulation framework is designed for boyden invasion chamber in experiments and based on a mathematical model that describes how tumor cells interact with neutrophils and N2 TANs can promote tumor cell invasion. We demonstrate that the efficacy of anti-tumor (anti-invasion) drugs depend on this critical communication and N1 → N2 landscapes of stimulated neutrophils.

scholarly journals AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis

Cell Stress ◽  
2020 ◽  
Vol 4 (12) ◽  
pp. 273-277
Author(s):  
Zhen Cai ◽  
Danni Peng ◽  
Hui-Kuan Lin
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Cancer Metabolism ◽  
Cancer Metastasis ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Pyruvate Metabolism ◽  
Primary Tumors ◽  
And Oxidative Stress

Cancer represents the leading public health problem throughout the world. Globally, about one out of six deaths is related to cancer, which is largely due to the metastatic lesions. However, there are no effective strategies for targeting cancer metastasis. Identification of the key druggable targets maintaining metastasis is crucial for cancer treatment. In our recent study (Cai et al. (2020), Mol Cell, doi: 10.1016/j.molcel.2020.09.018), we found that activity of AMPK was enriched in metastatic tumors compared to primary tumors. Depletion of AMPK rendered cancer cells more sensitive to metabolic and oxidative stress, leading to the impairment of breast cancer lung metastasis. Activation of AMPK rewired cancer metabolism towards TCA cycle, which protects disseminated cancer cells from both metabolic and oxidative stress-induced cell death, and facilitates cancer metastasis. Further, AMPK critically maintained the activity of pyruvate dehydrogenase complex (PDH), the rate limiting enzyme involved in TCA cycle, thus favoring the pyruvate metabolism towards TCA cycle rather than converting it to lactate. Mechanistically, AMPK was shown to co-localize with PDHA, the catalytic subunit of PDH, in the mitochondrial matrix and directly triggered the phosphorylation of PDHA on Ser295 and Ser314. Hyper-phosphorylation of Ser295 and Ser314 of PDHA promotes lung metastasis through elevating activity of PDH. Of note, PDHA Ser314 phosphorylation abrogated the interaction between PDHA and PDHKs leading to the dephosphorylation on previously reported S293 site, whose phosphorylation serves as a negative signal for PDH activation, while S295 phosphorylation serves as an intrinsic catalytic site required for pyruvate metabolism. Our study presented the first evidence for the pro-metastatic property of the AMPK-PDH axis and advance our current understanding of how PDH is activated under physiological and pathological conditions.

scholarly journals Periostin gene expression in neu-positive breast cancer cells is regulated by a FGFR signaling cross talk with TGFβ/PI3K/AKT pathways

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Cédrik Labrèche ◽  
David P. Cook ◽  
John Abou-Hamad ◽  
Julia Pascoal ◽  
Benjamin R. Pryce ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Matricellular Protein ◽  
Stromal Compartment ◽  
Primary Tumors

Abstract Background Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be involved in various processes of tumor development, such as angiogenesis, invasion, cell survival and metastasis. The expression of Postn in breast cancer cells has been correlated with a more aggressive phenotype. Despite extensive research, it remains unclear how epithelial cancer cells regulate Postn expression. Methods Using murine tumor models and human TMAs, we have assessed the proportion of tumor samples that have acquired Postn expression in tumor cells. Using biochemical approaches and tumor cell lines derived from Neu+ murine primary tumors, we have identified major regulators of Postn gene expression in breast cancer cell lines. Results Here, we show that, while the stromal compartment typically always expresses Postn, about 50% of breast tumors acquire Postn expression in the epithelial tumor cells. Furthermore, using an in vitro model, we show a cross-regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In HER2-positive murine breast cancer cells, we found that basic FGF can repress Postn expression through a PKC-dependent pathway, while TGFβ can induce Postn expression in a SMAD-independent manner. Postn induction following the removal of the FGF-suppressive signal is dependent on PI3K/AKT signaling. Conclusion Overall, these results reveal a novel regulatory mechanism and shed light on how breast tumor cells acquire Postn expression. This complex regulation is likely to be cell type and cancer specific as well as have important therapeutic implications.

scholarly journals Chemotherapy-exacerbated Breast Cancer Metastasis: A Paradox Explainable by Stress Response

2018 ◽  
Author(s):  
Justin D. Middleton ◽  
Daniel G. Stover ◽  
Tsonwin Hai
Keyword(s):  
Breast Cancer ◽  
Stress Response ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Blood Stream ◽  
Breast Cancer Metastasis ◽  
Host Cells ◽  
Primary Tumors

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

scholarly journals Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

2019 ◽  
Author(s):  
Yeon Soo Kim ◽  
Piyushi Gupta-Vallur ◽  
Victoria M. Jones ◽  
Beth L. Worley ◽  
Sara Shimko ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Peritoneal Cavity ◽  
Antioxidant Defenses ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Anoikis Resistance ◽  
Primary Tumors ◽  
Context Dependent

ABSTRACTCells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

scholarly journals Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors

2016 ◽  
Vol 113 (8) ◽  
pp. 2223-2228 ◽  
Author(s):  
Eleonora Dondossola ◽  
Andrey S. Dobroff ◽  
Serena Marchiò ◽  
Marina Cardó-Vila ◽  
Hitomi Hosoya ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Anticancer Agents ◽  
Genetically Engineered ◽  
Mammary Adenocarcinoma ◽  
Metastatic Tumors ◽  
Necrosis Factor Alpha ◽  
Primary Tumors ◽  
Lung Carcinoma Cells

Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed “tumor self-seeding.” Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as “tumor self-targeting.” For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell–mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.

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