Pub Date : 2017-09-01Epub Date: 2017-06-22DOI: 10.1088/2057-1739/aa757b
Merlyn Pulikkathara, Colette Mark, Natasha Kumar, Ana Maria Zaske, Rita E Serda
Background: Applied radiofrequency (RF) energy induces hyperthermia in tissues, facilitating vascular perfusion This study explores the impact of RF radiation on the integrity of the luminal endothelium, and then predominately explores the impact of altering the conductivity of biologically-relevant solutions on RF-induced heating rates and cell death. The ability of cells to survive high sucrose (i.e. hyperosmotic conditions) to achieve lower conductivity as a mechanism for directing hyperthermia is evaluated.
Methods: RF radiation was generated using a capacitively-coupled radiofrequency system operating at 13.56 MHz. Temperatures were recorded using a FLIR SC 6000 infrared camera.
Results: RF radiation reduced cell-to-cell connections among endothelial cells and altered cell morphology towards a more rounded appearance at temperatures reported to cause in vivo vessel deformation. Isotonic solutions containing high sucrose and low levels of NaCl displayed low conductivity and faster heating rates compared to high salt solutions. Heating rates were positively correlated with cell death. Addition of sucrose to serum similarly reduced conductivity and increased heating rates in a dose-dependent manner. Cellular proliferation was normal for cells grown in media supplemented with 125 mM sucrose for 24 hours or for cells grown in 750 mM sucrose for 10 minutes followed by a 24 h recovery period.
Conclusions: Sucrose is known to form weak hydrogen bonds in fluids as opposed to ions, freeing water molecules to rotate in an oscillating field of electromagnetic radiation and contributing to heat induction. The ability of cells to survive temporal exposures to hyperosmotic (i.e. elevated sucrose) conditions creates an opportunity to use sucrose or other saccharides to selectively elevate heating in specific tissues upon exposure to a radiofrequency field.
{"title":"Sucrose modulation of radiofrequency-induced heating rates and cell death.","authors":"Merlyn Pulikkathara, Colette Mark, Natasha Kumar, Ana Maria Zaske, Rita E Serda","doi":"10.1088/2057-1739/aa757b","DOIUrl":"https://doi.org/10.1088/2057-1739/aa757b","url":null,"abstract":"<p><strong>Background: </strong>Applied radiofrequency (RF) energy induces hyperthermia in tissues, facilitating vascular perfusion This study explores the impact of RF radiation on the integrity of the luminal endothelium, and then predominately explores the impact of altering the conductivity of biologically-relevant solutions on RF-induced heating rates and cell death. The ability of cells to survive high sucrose (i.e. hyperosmotic conditions) to achieve lower conductivity as a mechanism for directing hyperthermia is evaluated.</p><p><strong>Methods: </strong>RF radiation was generated using a capacitively-coupled radiofrequency system operating at 13.56 MHz. Temperatures were recorded using a FLIR SC 6000 infrared camera.</p><p><strong>Results: </strong>RF radiation reduced cell-to-cell connections among endothelial cells and altered cell morphology towards a more rounded appearance at temperatures reported to cause <i>in vivo</i> vessel deformation. Isotonic solutions containing high sucrose and low levels of NaCl displayed low conductivity and faster heating rates compared to high salt solutions. Heating rates were positively correlated with cell death. Addition of sucrose to serum similarly reduced conductivity and increased heating rates in a dose-dependent manner. Cellular proliferation was normal for cells grown in media supplemented with 125 mM sucrose for 24 hours or for cells grown in 750 mM sucrose for 10 minutes followed by a 24 h recovery period.</p><p><strong>Conclusions: </strong>Sucrose is known to form weak hydrogen bonds in fluids as opposed to ions, freeing water molecules to rotate in an oscillating field of electromagnetic radiation and contributing to heat induction. The ability of cells to survive temporal exposures to hyperosmotic (i.e. elevated sucrose) conditions creates an opportunity to use sucrose or other saccharides to selectively elevate heating in specific tissues upon exposure to a radiofrequency field.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/aa757b","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35644414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gino In, Jeremy Mason, Sonia Lin, Paul K Newton, Peter Kuhn, Jorge Nieva
Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (EGFR), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst EGFR mutated (EGFRm) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to EGFR wild type (EGFRwt). The brain was classified as an anatomic "sponge", with a higher ratio of incoming to outgoing spread, for EGFRm NSCLC. Bone metastases were more commonly identified in EGFRwt patients. Our study supports a link between the anatomical and molecular characterization of lung metastatic cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.
癌症通常根据致癌驱动因素的存在进行分类,如表皮生长因子受体(EGFR),而不是解剖分布模式。虽然转移性传播可能看起来是一个随机和不可预测的过程,但我们探索了使用其可量化性质来描述和比较不同疾病子集的可能性。我们建立了南加州大学诺里斯综合癌症中心和洛杉矶县医疗中心664名非小细胞肺癌(NSCLC)患者的数据库。Markov数学模型用于在疾病进展的每个时间点以时空方式评估转移部位。我们的研究结果确定,与EGFR野生型(EGFR-wt)相比,在EGFR突变(EGFR-m)的NSCLC患者中,外显子19缺失或外显子21 L858R突变的原发性肺病通过肺转移到大脑的优先模式。对于EGFR m NSCLC,大脑被归类为解剖上的“海绵”,具有较高的传入和传出扩散比率。骨转移更常见于EGFR-wt患者。我们的研究支持了肺转移性癌症的解剖学和分子特征之间的联系。基于基因型特异性分析,更好地理解导致解剖扩散不一致模式的差异生物学,有可能改善个性化肿瘤学护理。
{"title":"Development of metastatic brain disease involves progression through lung metastases in <i>EGFR</i> mutated non-small cell lung cancer.","authors":"Gino In, Jeremy Mason, Sonia Lin, Paul K Newton, Peter Kuhn, Jorge Nieva","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (<i>EGFR</i>), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst <i>EGFR</i> mutated (<i>EGFR</i> <sup>m</sup>) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to <i>EGFR</i> wild type (<i>EGFR</i> <sup>wt</sup>). The brain was classified as an anatomic \"sponge\", with a higher ratio of incoming to outgoing spread, for <i>EGFR</i> <sup>m</sup> NSCLC. Bone metastases were more commonly identified in <i>EGFR</i> <sup>wt</sup> patients. Our study supports a link between the anatomical and molecular characterization of lung metastatic cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166474/pdf/nihms916878.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41167823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-07-13DOI: 10.1088/2057-1739/AA7A8D
G. In, J. Mason, Sonia Lin, P. Newton, P. Kuhn, J. Nieva
Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (EGFR), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst EGFR mutated (EGFR m) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to EGFR wild type (EGFR wt). The brain was classified as an anatomic "sponge", with a higher ratio of incoming to outgoing spread, for EGFR m NSCLC. Bone metastases were more commonly identified in EGFR wt patients. Our study supports a link between the anatomical and molecular characterization of lung metastatic cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.
{"title":"Development of metastatic brain disease involves progression through lung metastases in EGFR mutated non-small cell lung cancer.","authors":"G. In, J. Mason, Sonia Lin, P. Newton, P. Kuhn, J. Nieva","doi":"10.1088/2057-1739/AA7A8D","DOIUrl":"https://doi.org/10.1088/2057-1739/AA7A8D","url":null,"abstract":"Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (EGFR), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst EGFR mutated (EGFR m) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to EGFR wild type (EGFR wt). The brain was classified as an anatomic \"sponge\", with a higher ratio of incoming to outgoing spread, for EGFR m NSCLC. Bone metastases were more commonly identified in EGFR wt patients. Our study supports a link between the anatomical and molecular characterization of lung metastatic cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/AA7A8D","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44025018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-06-01Epub Date: 2017-05-17DOI: 10.1088/2057-1739/aa6c05
Joanna L Sylman, Annachiara Mitrugno, Garth W Tormoen, Todd H Wagner, Parag Mallick, Owen J T McCarty
Platelets are anucleate cells in the blood at concentrations of 150,000 to 400,000 cells/µL and play a key role in hemostasis. Several studies have suggested that platelets contribute to cancer progression and cancer-associated thrombosis. In this review, we provide an overview of the biochemical and biophysical mechanisms by which platelets interact with cancer cells and review the evidence supporting a role for platelet-enhanced metastasis of cancer, and venous thromboembolism (VTE) in patients with cancer. We discuss the potential for and limitations of platelet counts to discriminate cancer disease burden and prognosis. Lastly, we consider more advanced diagnostic approaches to improve studies on the interaction between the hemostatic system and cancer cells.
{"title":"Platelet count as a predictor of metastasis and venous thromboembolism in patients with cancer.","authors":"Joanna L Sylman, Annachiara Mitrugno, Garth W Tormoen, Todd H Wagner, Parag Mallick, Owen J T McCarty","doi":"10.1088/2057-1739/aa6c05","DOIUrl":"https://doi.org/10.1088/2057-1739/aa6c05","url":null,"abstract":"<p><p>Platelets are anucleate cells in the blood at concentrations of 150,000 to 400,000 cells/µL and play a key role in hemostasis. Several studies have suggested that platelets contribute to cancer progression and cancer-associated thrombosis. In this review, we provide an overview of the biochemical and biophysical mechanisms by which platelets interact with cancer cells and review the evidence supporting a role for platelet-enhanced metastasis of cancer, and venous thromboembolism (VTE) in patients with cancer. We discuss the potential for and limitations of platelet counts to discriminate cancer disease burden and prognosis. Lastly, we consider more advanced diagnostic approaches to improve studies on the interaction between the hemostatic system and cancer cells.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/aa6c05","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35556912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-02-23DOI: 10.1088/2057-1739/aa5cf1
Paula Cunnea, Sally Gowers, James E Moore, Emmanuel Drakakis, Martyn Boutelle, Christina Fotopoulou
Epithelial Ovarian cancer (EOC) is the fifth most common cause of cancer death in females in the UK. It has long been recognized to be a set of heterogeneous diseases, with high grade serous being the most common subtype. The majority of patients with EOC present at an advanced stage (FIGO III-IV), and have the largest risk for disease recurrence from which a high percentage will develop resistance to chemotherapy. Despite continual advances in diagnostics, imaging, surgery and treatment of EOC, there has been little variation in the survival rates for patients with EOC. In this review we will introduce novel bioengineering advances in modelling the lymphatic system and real-time tissue monitoring to improve the clinical and therapeutic outcome for patients with EOC. We discuss the advent of the non-invasive "liquid biopsy" in the surveillance of patients undergoing treatment and follow-up. Finally, we present new bioengineering advances for palliative care of patients to lessen symptoms of patients with ascites and improve quality of life.
{"title":"Review article: Novel technologies in the treatment and monitoring of advanced and relapsed epithelial ovarian cancer.","authors":"Paula Cunnea, Sally Gowers, James E Moore, Emmanuel Drakakis, Martyn Boutelle, Christina Fotopoulou","doi":"10.1088/2057-1739/aa5cf1","DOIUrl":"https://doi.org/10.1088/2057-1739/aa5cf1","url":null,"abstract":"<p><p>Epithelial Ovarian cancer (EOC) is the fifth most common cause of cancer death in females in the UK. It has long been recognized to be a set of heterogeneous diseases, with high grade serous being the most common subtype. The majority of patients with EOC present at an advanced stage (FIGO III-IV), and have the largest risk for disease recurrence from which a high percentage will develop resistance to chemotherapy. Despite continual advances in diagnostics, imaging, surgery and treatment of EOC, there has been little variation in the survival rates for patients with EOC. In this review we will introduce novel bioengineering advances in modelling the lymphatic system and real-time tissue monitoring to improve the clinical and therapeutic outcome for patients with EOC. We discuss the advent of the non-invasive \"liquid biopsy\" in the surveillance of patients undergoing treatment and follow-up. Finally, we present new bioengineering advances for palliative care of patients to lessen symptoms of patients with ascites and improve quality of life.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/aa5cf1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35893559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-11-29DOI: 10.1088/2057-1739/aa9263
Danielle J LaValley, Matthew R Zanotelli, Francois Bordeleau, Wenjun Wang, Samantha C Schwager, Cynthia A Reinhart-King
Vascular endothelial growth factor (VEGF) can mediate endothelial cell migration, proliferation, and angiogenesis. During cancer progression, VEGF production is often increased to stimulate the growth of new blood vessels to supply growing tumors with the additional oxygen and nutrients they require. Extracellular matrix stiffening also occurs during tumor progression, however, the crosstalk between tumor mechanics and VEGF signaling remains poorly understood. Here, we show that matrix stiffness heightens downstream endothelial cell response to VEGF by altering VEGF receptor-2 (VEGFR-2) internalization, and this effect is influenced by cell confluency. In sub-confluent endothelial monolayers, VEGFR-2 levels, but not VEGFR-2 phosphorylation, are influenced by matrix rigidity. Interestingly, more compliant matrices correlated with increased expression and clustering of VEGFR-2; however, stiffer matrices induced increased VEGFR-2 internalization. These effects are most likely due to actin-mediated contractility, as inhibiting ROCK on stiff substrates increased VEGFR-2 clustering and decreased internalization. Additionally, increasing matrix stiffness elevates ERK 1/2 phosphorylation, resulting in increased cell proliferation. Moreover, cells on stiff matrices generate more actin stress fibers than on compliant substrates, and the addition of VEGF stimulates an increase in fiber formation regardless of stiffness. In contrast, once endothelial cells reached confluency, stiffness-enhanced VEGF signaling was no longer observed. Together, these data show a complex effect of VEGF and matrix mechanics on VEGF-induced signaling, receptor dynamics, and cell proliferation that is mediated by cell confluency.
{"title":"Matrix Stiffness Enhances VEGFR-2 Internalization, Signaling, and Proliferation in Endothelial Cells.","authors":"Danielle J LaValley, Matthew R Zanotelli, Francois Bordeleau, Wenjun Wang, Samantha C Schwager, Cynthia A Reinhart-King","doi":"10.1088/2057-1739/aa9263","DOIUrl":"https://doi.org/10.1088/2057-1739/aa9263","url":null,"abstract":"<p><p>Vascular endothelial growth factor (VEGF) can mediate endothelial cell migration, proliferation, and angiogenesis. During cancer progression, VEGF production is often increased to stimulate the growth of new blood vessels to supply growing tumors with the additional oxygen and nutrients they require. Extracellular matrix stiffening also occurs during tumor progression, however, the crosstalk between tumor mechanics and VEGF signaling remains poorly understood. Here, we show that matrix stiffness heightens downstream endothelial cell response to VEGF by altering VEGF receptor-2 (VEGFR-2) internalization, and this effect is influenced by cell confluency. In sub-confluent endothelial monolayers, VEGFR-2 levels, but not VEGFR-2 phosphorylation, are influenced by matrix rigidity. Interestingly, more compliant matrices correlated with increased expression and clustering of VEGFR-2; however, stiffer matrices induced increased VEGFR-2 internalization. These effects are most likely due to actin-mediated contractility, as inhibiting ROCK on stiff substrates increased VEGFR-2 clustering and decreased internalization. Additionally, increasing matrix stiffness elevates ERK 1/2 phosphorylation, resulting in increased cell proliferation. Moreover, cells on stiff matrices generate more actin stress fibers than on compliant substrates, and the addition of VEGF stimulates an increase in fiber formation regardless of stiffness. In contrast, once endothelial cells reached confluency, stiffness-enhanced VEGF signaling was no longer observed. Together, these data show a complex effect of VEGF and matrix mechanics on VEGF-induced signaling, receptor dynamics, and cell proliferation that is mediated by cell confluency.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/aa9263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35908188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-07-28DOI: 10.1088/2057-1739/aa7e86
R J Seager, Cynthia Hajal, Fabian Spill, Roger D Kamm, Muhammad H Zaman
In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro-and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.
{"title":"Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression.","authors":"R J Seager, Cynthia Hajal, Fabian Spill, Roger D Kamm, Muhammad H Zaman","doi":"10.1088/2057-1739/aa7e86","DOIUrl":"https://doi.org/10.1088/2057-1739/aa7e86","url":null,"abstract":"<p><p>In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro-and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/aa7e86","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36373150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-09-01Epub Date: 2016-09-20DOI: 10.1088/2057-1739/2/3/035004
C Schäfer, A Mohan, W Burford, M K Driscoll, A T Ludlow, W E Wright, J W Shay, G Danuser
Introduction: Oncogenic Kras mutations are important drivers of lung cancer development and metastasis. They are known to activate numerous cellular signaling pathways implicated in enhanced proliferation, survival, tumorigenicity and motility during malignant progression.
Objectives: Most previous studies of Kras in cancer have focused on the comparison of cell states in the absence or presence of oncogenic Kras mutations. Here we show that differential expression of the constitutively active mutation KrasV12 has profound effects on cell morphology and motility that drive metastatic processes.
Methods: The study relies on lung cancer cell transformation models, patient-derived lung cancer cell lines, and human lung tumor sections combined with molecular biology techniques, live-cell imaging and staining methods.
Results: Our analysis shows two cell functional states driven by KrasV12 protein levels: a non-motile state associated with high KrasV12 levels and tumorigenicity, and a motile state associated with low KrasV12 levels and cell dissemination. Conversion between the states is conferred by differential activation of a mechano-sensitive double-negative feedback between KrasV12/ERK/Myosin II and matrix-adhesion signaling. KrasV12 expression levels change upon cues such as hypoxia and integrin-mediated cell-matrix adhesion, rendering KrasV12 levels an integrator of micro-environmental signals that translate into cellular function. By live cell imaging of tumor models we observe shedding of mixed high and low KrasV12 expressers forming multi-functional collectives with potentially optimal metastatic properties composed of a highly mobile and a highly tumorigenic unit.
Discussion: Together these data highlight previously unappreciated roles for the quantitative effects of expression level variation of oncogenic signaling molecules in conferring fundamental alterations in cell function regulation required for cancer progression.
{"title":"Differential Kras<sup>V12</sup> protein levels control a switch regulating lung cancer cell morphology and motility.","authors":"C Schäfer, A Mohan, W Burford, M K Driscoll, A T Ludlow, W E Wright, J W Shay, G Danuser","doi":"10.1088/2057-1739/2/3/035004","DOIUrl":"https://doi.org/10.1088/2057-1739/2/3/035004","url":null,"abstract":"<p><strong>Introduction: </strong>Oncogenic Kras mutations are important drivers of lung cancer development and metastasis. They are known to activate numerous cellular signaling pathways implicated in enhanced proliferation, survival, tumorigenicity and motility during malignant progression.</p><p><strong>Objectives: </strong>Most previous studies of Kras in cancer have focused on the comparison of cell states in the absence or presence of oncogenic Kras mutations. Here we show that differential expression of the constitutively active mutation Kras<sup>V12</sup> has profound effects on cell morphology and motility that drive metastatic processes.</p><p><strong>Methods: </strong>The study relies on lung cancer cell transformation models, patient-derived lung cancer cell lines, and human lung tumor sections combined with molecular biology techniques, live-cell imaging and staining methods.</p><p><strong>Results: </strong>Our analysis shows two cell functional states driven by Kras<sup>V12</sup> protein levels: a non-motile state associated with high Kras<sup>V12</sup> levels and tumorigenicity, and a motile state associated with low Kras<sup>V12</sup> levels and cell dissemination. Conversion between the states is conferred by differential activation of a mechano-sensitive double-negative feedback between Kras<sup>V12</sup>/ERK/Myosin II and matrix-adhesion signaling. Kras<sup>V12</sup> expression levels change upon cues such as hypoxia and integrin-mediated cell-matrix adhesion, rendering Kras<sup>V12</sup> levels an integrator of micro-environmental signals that translate into cellular function. By live cell imaging of tumor models we observe shedding of mixed high and low Kras<sup>V12</sup> expressers forming multi-functional collectives with potentially optimal metastatic properties composed of a highly mobile and a highly tumorigenic unit.</p><p><strong>Discussion: </strong>Together these data highlight previously unappreciated roles for the quantitative effects of expression level variation of oncogenic signaling molecules in conferring fundamental alterations in cell function regulation required for cancer progression.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/2/3/035004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35532413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-09-01Epub Date: 2016-07-04DOI: 10.1088/2057-1739/2/3/035002
Jeffrey West, Zaki Hasnain, Jeremy Mason, Paul K Newton
Tumor development is an evolutionary process in which a heterogeneous population of cells with different growth capabilities compete for resources in order to gain a proliferative advantage. What are the minimal ingredients needed to recreate some of the emergent features of such a developing complex ecosystem? What is a tumor doing before we can detect it? We outline a mathematical model, driven by a stochastic Moran process, in which cancer cells and healthy cells compete for dominance in the population. Each are assigned payoffs according to a Prisoner's Dilemma evolutionary game where the healthy cells are the cooperators and the cancer cells are the defectors. With point mutational dynamics, heredity, and a fitness landscape controlling birth and death rates, natural selection acts on the cell population and simulated 'cancer-like' features emerge, such as Gompertzian tumor growth driven by heterogeneity, the log-kill law which (linearly) relates therapeutic dose density to the (log) probability of cancer cell survival, and the Norton-Simon hypothesis which (linearly) relates tumor regression rates to tumor growth rates. We highlight the utility, clarity, and power that such models provide, despite (and because of) their simplicity and built-in assumptions.
{"title":"The prisoner's dilemma as a cancer model.","authors":"Jeffrey West, Zaki Hasnain, Jeremy Mason, Paul K Newton","doi":"10.1088/2057-1739/2/3/035002","DOIUrl":"10.1088/2057-1739/2/3/035002","url":null,"abstract":"<p><p>Tumor development is an evolutionary process in which a heterogeneous population of cells with different growth capabilities compete for resources in order to gain a proliferative advantage. What are the minimal ingredients needed to recreate some of the emergent features of such a developing complex ecosystem? What is a tumor doing before we can detect it? We outline a mathematical model, driven by a stochastic Moran process, in which cancer cells and healthy cells compete for dominance in the population. Each are assigned payoffs according to a Prisoner's Dilemma evolutionary game where the healthy cells are the cooperators and the cancer cells are the defectors. With point mutational dynamics, heredity, and a fitness landscape controlling birth and death rates, natural selection acts on the cell population and simulated 'cancer-like' features emerge, such as Gompertzian tumor growth driven by heterogeneity, the log-kill law which (linearly) relates therapeutic dose density to the (log) probability of cancer cell survival, and the Norton-Simon hypothesis which (linearly) relates tumor regression rates to tumor growth rates. We highlight the utility, clarity, and power that such models provide, despite (and because of) their simplicity and built-in assumptions.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701760/pdf/nihms913703.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35644413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-06-01Epub Date: 2016-05-19DOI: 10.1088/2057-1739/2/2/025001
R M Lee, C H Stuelten, C A Parent, W Losert
Introduction: Migratory phenotypes of metastasizing tumor cells include single and collective cell migration. While migration of tumor cells is generally less cooperative than that of normal epithelial cells, our understanding of precisely how they differ in long time behavior is incomplete.
Objectives: We measure in a model system how cancer progression affects collective migration on long time scales, and determine how perturbation of cell-cell adhesions, specifically reduced E-cadherin expression, affects the collective migration phenotype.
Methods: Time lapse imaging of cellular sheets and particle image velocimetry (PIV) are used to quantitatively study the dynamics of cell motion over ten hours. Long time dynamics are measured via finite time Lyapunov exponents (FTLE) and changes in FTLE with time.
Results: We find that non-malignant MCF10A cells are distinguished from malignant MCF10CA1a cells by both their short time (minutes) and long time (hours) dynamics. In addition, short time dynamics distinguish non-malignant E-cadherin knockdown cells from the control, but long time dynamics and increasing spatial correlations remain unchanged.
Discussion: Epithelial sheet collective behavior includes long time dynamics that cannot be captured by metrics that assess cooperativity based on short time dynamics, such as instantaneous speed or directionality. The use of metrics incorporating migration data over hours instead of minutes allows us to more precisely describe how E-cadherin, a clinically relevant adhesion molecule, affects collective migration. We predict that the long time scale metrics described here will be more robust and predictive of malignant behavior than analysis of instantaneous velocity fields alone.
{"title":"Collective cell migration over long time scales reveals distinct phenotypes.","authors":"R M Lee, C H Stuelten, C A Parent, W Losert","doi":"10.1088/2057-1739/2/2/025001","DOIUrl":"https://doi.org/10.1088/2057-1739/2/2/025001","url":null,"abstract":"<p><strong>Introduction: </strong>Migratory phenotypes of metastasizing tumor cells include single and collective cell migration. While migration of tumor cells is generally less cooperative than that of normal epithelial cells, our understanding of precisely how they differ in long time behavior is incomplete.</p><p><strong>Objectives: </strong>We measure in a model system how cancer progression affects collective migration on long time scales, and determine how perturbation of cell-cell adhesions, specifically reduced E-cadherin expression, affects the collective migration phenotype.</p><p><strong>Methods: </strong>Time lapse imaging of cellular sheets and particle image velocimetry (PIV) are used to quantitatively study the dynamics of cell motion over ten hours. Long time dynamics are measured via finite time Lyapunov exponents (FTLE) and changes in FTLE with time.</p><p><strong>Results: </strong>We find that non-malignant MCF10A cells are distinguished from malignant MCF10CA1a cells by both their short time (minutes) and long time (hours) dynamics. In addition, short time dynamics distinguish non-malignant E-cadherin knockdown cells from the control, but long time dynamics and increasing spatial correlations remain unchanged.</p><p><strong>Discussion: </strong>Epithelial sheet collective behavior includes long time dynamics that cannot be captured by metrics that assess cooperativity based on short time dynamics, such as instantaneous speed or directionality. The use of metrics incorporating migration data over hours instead of minutes allows us to more precisely describe how E-cadherin, a clinically relevant adhesion molecule, affects collective migration. We predict that the long time scale metrics described here will be more robust and predictive of malignant behavior than analysis of instantaneous velocity fields alone.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/2/2/025001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36011341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}