scholarly journals Epithelial-mesenchymal plasticity: How have quantitative mathematical models helped improve our understanding?

2017 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Satyendra C Tripathi ◽  
Jason A Somarelli ◽  
Samir M Hanash ◽  
Herbert Levine
Keyword(s):  
Phenotypic Plasticity ◽  
Mathematical Models ◽  
Tumor Progression ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Invasion And Metastasis ◽  
Hallmarks Of Cancer ◽  
Mesenchymal Phenotype ◽  
Extracellular Signals ◽  
Clinical Challenge

AbstractPhenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well-studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune-evasion, and invasion and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally-verified molecular mechanisms and act as ‘ hypothesis-generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive epithelial-mesenchymal plasticity at both the single-cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.

scholarly journals Biological Functions of the Genes in the Mammaprint Breast Cancer Profile Reflect the Hallmarks of Cancer

2010 ◽  
Vol 5 ◽  
pp. BMI.S6184 ◽  
Author(s):  
Sun Tian ◽  
Paul Roepman ◽  
Laura J van't Veer ◽  
Rene Bernards ◽  
Femke De Snoo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Biological Activities ◽  
Tumor Biology ◽  
Molecular Signature ◽  
Biological Functions ◽  
Hallmarks Of Cancer ◽  
Network Analyses

Background MammaPrint was developed as a diagnostic tool to predict risk of breast cancer metastasis using the expression of 70 genes. To better understand the tumor biology assessed by MammaPrint, we interpreted the biological functions of the 70-genes and showed how the genes reflect the six hallmarks of cancer as defined by Hanahan and Weinberg. Results We used a bottom-up system biology approach to elucidate how the cellular processes reflected by the 70-genes work together to regulate tumor activities and progression. The biological functions of the genes were analyzed using literature research and several bioinformatics tools. Protein-protein interaction network analyses indicated that the 70-genes form highly interconnected networks and that their expression levels are regulated by key tumorigenesis related genes such as TP53, RB1, MYC, JUN and CDKN2A. The biological functions of the genes could be associated with the essential steps necessary for tumor progression and metastasis, and cover the six well-defined hallmarks of cancer, reflecting the acquired malignant characteristics of a cancer cell along with tumor progression and metastasis-related biological activities. Conclusion Genes in the MammaPrint gene signature comprehensively measure the six hallmarks of cancer-related biology. This finding establishes a link between a molecular signature and the underlying molecular mechanisms of tumor cell progression and metastasis.

scholarly journals Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

2015 ◽  
Vol 23 (2) ◽  
pp. R85-R111 ◽  
Author(s):  
Annu Makker ◽  
Madhu Mati Goel
Keyword(s):  
High Risk ◽  
Tumor Progression ◽  
Endometrial Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Early Stage ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Endometrioid Endometrial Carcinoma

Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70–80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial–mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis – the most fatal consequence of endometrial carcinogenesis.

scholarly journals Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
María Romina Girotti ◽  
Mariana Salatino ◽  
Tomás Dalotto-Moreno ◽  
Gabriel A. Rabinovich
Keyword(s):  
Immune Responses ◽  
Tumor Progression ◽  
Stromal Cells ◽  
Human Cancer ◽  
Invasion And Metastasis ◽  
Hallmarks Of Cancer ◽  
Evolutionarily Conserved ◽  
Proliferative Signaling ◽  
Organizing Principles

Hanahan and Weinberg have proposed 10 organizing principles that enable growth and metastatic dissemination of cancer cells. These distinctive and complementary capabilities, defined as the “hallmarks of cancer,” include the ability of tumor cells and their microenvironment to sustain proliferative signaling, evade growth suppressors, resist cell death, promote replicative immortality, induce angiogenesis, support invasion and metastasis, reprogram energy metabolism, induce genomic instability and inflammation, and trigger evasion of immune responses. These common features are hierarchically regulated through different mechanisms, including those involving glycosylation-dependent programs that influence the biological and clinical impact of each hallmark. Galectins, an evolutionarily conserved family of glycan-binding proteins, have broad influence in tumor progression by rewiring intracellular and extracellular circuits either in cancer or stromal cells, including immune cells, endothelial cells, and fibroblasts. In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.

scholarly journals Acute vs. Chronic vs. Cyclic Hypoxia: Their Differential Dynamics, Molecular Mechanisms, and Effects on Tumor Progression

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 339 ◽  
Author(s):  
Saxena ◽  
Jolly
Keyword(s):  
Tumor Progression ◽  
Intermittent Hypoxia ◽  
Molecular Mechanisms ◽  
Total Duration ◽  
Adaptation To Hypoxia ◽  
Hallmarks Of Cancer ◽  
Obstructive Sleep ◽  
Risk Of Cancer

Hypoxia has been shown to increase the aggressiveness and severity of tumor progression. Along with chronic and acute hypoxic regions, solid tumors contain regions of cycling hypoxia (also called intermittent hypoxia or IH). Cyclic hypoxia is mimicked in vitro and in vivo by periodic exposure to cycles of hypoxia and reoxygenation (H–R cycles). Compared to chronic hypoxia, cyclic hypoxia has been shown to augment various hallmarks of cancer to a greater extent: angiogenesis, immune evasion, metastasis, survival etc. Cycling hypoxia has also been shown to be the major contributing factor in increasing the risk of cancer in obstructive sleep apnea (OSA) patients. Here, we first compare and contrast the effects of acute, chronic and intermittent hypoxia in terms of molecular pathways activated and the cellular processes affected. We highlight the underlying complexity of these differential effects and emphasize the need to investigate various combinations of factors impacting cellular adaptation to hypoxia: total duration of hypoxia, concentration of oxygen (O2), and the presence of and frequency of H–R cycles. Finally, we summarize the effects of cycling hypoxia on various hallmarks of cancer highlighting their dependence on the abovementioned factors. We conclude with a call for an integrative and rigorous analysis of the effects of varying extents and durations of hypoxia on cells, including tools such as mechanism-based mathematical modelling and microfluidic setups.

scholarly journals Curcumin as an Adjuvant to Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Silpita Paul ◽  
Gaurisankar Sa
Keyword(s):  
Immune Evasion ◽  
Immune Escape ◽  
Growth Inhibitors ◽  
Invasion And Metastasis ◽  
Hallmarks Of Cancer ◽  
Tumor Immune Escape ◽  
Tissue Invasion ◽  
Anti Cancer ◽  
Immune Adjuvant ◽  
Over Time

The components of the immune system play a very sincere and crucial role in combating tumors. However, despite their firm efforts of elimination, tumor cells cleverly escape the surveillance process by adopting several immune evasion mechanisms. The conversion of immunogenicity of tumor microenvironment into tolerogenic is considered as a prime reason for tumor immune escape. Therapeutically, different immunotherapies have been adopted to block such immune escaping routes along with better clinical outcomes. Still, the therapies are haunted by several drawbacks. Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor’s way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes.

scholarly journals Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis

Oncogene ◽  
2021 ◽  
Author(s):  
Satoshi Takagi ◽  
Yuki Sasaki ◽  
Sumie Koike ◽  
Ai Takemoto ◽  
Yosuke Seto ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Pulmonary Metastasis ◽  
Lysophosphatidic Acid ◽  
Therapeutic Intervention ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Osteosarcoma Cells ◽  
Invasion And Metastasis ◽  
Platelet Releasate

AbstractOsteosarcoma is the most common primary malignant bone cancer, with high rates of pulmonary metastasis. Osteosarcoma patients with pulmonary metastasis have worse prognosis than those with localized disease, leading to dramatically reduced survival rates. Therefore, understanding the biological characteristics of metastatic osteosarcoma and the molecular mechanisms of invasion and metastasis of osteosarcoma cells will lead to the development of innovative therapeutic intervention for advanced osteosarcoma. Here, we identified that osteosarcoma cells commonly exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets promote the invasiveness of osteosarcoma cells. Given that heat-denatured platelet releasate maintained the ability to promote osteosarcoma invasion, we focused on heat-tolerant molecules, such as lipid mediators in the platelet releasate. Osteosarcoma-induced platelet activation leads to abundant lysophosphatidic acid (LPA) release. Exposure to LPA or platelet releasate induced morphological changes and increased invasiveness of osteosarcoma cells. By analyzing publicly available transcriptome datasets and our in-house osteosarcoma patient-derived xenograft tumors, we found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma. LPAR1 gene KO in osteosarcoma cells abolished the platelet-mediated osteosarcoma invasion in vitro and the formation of early pulmonary metastatic foci in experimental pulmonary metastasis models. Of note, the pharmacological inhibition of LPAR1 by the orally available LPAR1 antagonist, ONO-7300243, prevented pulmonary metastasis of osteosarcoma in the mouse models. These results indicate that the LPA–LPAR1 axis is essential for the osteosarcoma invasion and metastasis, and targeting LPAR1 would be a promising therapeutic intervention for advanced osteosarcoma.

Angiogenesis: molecular mechanisms and functional interactions

2003 ◽  
Vol 89 (01) ◽  
pp. 190-197 ◽  
Author(s):  
Georg Breier ◽  
Hellmut Augustin
Keyword(s):  
Growth Factors ◽  
Research Program ◽  
Tumor Invasion ◽  
Molecular Mechanisms ◽  
Precursor Cells ◽  
Invasion And Metastasis ◽  
Angiogenic Growth Factors ◽  
Cell Contacts ◽  
Functional Interactions ◽  
Biannual Meeting

SummaryThe German Priority Research Program “Angiogenesis” (www.angiogenese.de) hosts a biannual meeting in the Kloster Seeon in Southern Germany. The 2nd Kloster Seeon Meeting “Angiogenesis: Molecular Mechanisms and Functional Interactions” was held in September 2002. It included sessions on hypoxia, the biology of endothelial precursor cells, angiogenic growth factors including VEGFs, the angiopoietins, ephrins, and FGFs, mechanisms of vascular sprouting and cell-cell contacts during angiogenesis, angiogenic signaling, lymphangiogenesis, angiogenesis during tumor invasion and metastasis, and on novel angiomanipulatory therapies. This report summarizes the key findings reported during the platform presentations of the meeting.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Tumor progression by immune evasion in melanoma

Cancer ◽  
2010 ◽  
Vol 116 (7) ◽  
pp. 1623-1625 ◽  
Author(s):  
Mohammed Kashani-Sabet
Keyword(s):  
Tumor Progression ◽  
Immune Evasion
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