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1.
Proc Natl Acad Sci U S A ; 120(42): e2303774120, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37816052

RESUMO

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.


Assuntos
Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Adipócitos/metabolismo , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Rosiglitazona/farmacologia
2.
bioRxiv ; 2023 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-37333362

RESUMO

Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporating stromal reprogramming.

3.
Gastroenterology ; 165(2): 374-390, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37196797

RESUMO

BACKGROUND & AIMS: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia. METHODS: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts. RESULTS: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα+ subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia-induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition. CONCLUSIONS: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages.


Assuntos
Mucosa Gástrica , Neoplasias Gástricas , Humanos , Mucosa Gástrica/patologia , Neoplasias Gástricas/patologia , Hiperplasia , Metaplasia/patologia , Fibroblastos/metabolismo
4.
Proteomics ; 23(7-8): e2200021, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36228107

RESUMO

Early events associated with chronic inflammation and cancer involve significant remodeling of the extracellular matrix (ECM), which greatly affects its composition and functional properties. Using lung squamous cell carcinoma (LSCC), a chronic inflammation-associated cancer (CIAC), we optimized a robust proteomic pipeline to discover potential biomarker signatures and protein changes specifically in the stroma. We combined ECM enrichment from fresh human tissues, data-independent acquisition (DIA) strategies, and stringent statistical processing to analyze "Tumor" and matched adjacent histologically normal ("Matched Normal") tissues from patients with LSCC. Overall, 1802 protein groups were quantified with at least two unique peptides, and 56% of those proteins were annotated as "extracellular." Confirming dramatic ECM remodeling during CIAC progression, 529 proteins were significantly altered in the "Tumor" compared to "Matched Normal" tissues. The signature was typified by a coordinated loss of basement membrane proteins and small leucine-rich proteins. The dramatic increase in the stromal levels of SERPINH1/heat shock protein 47, that was discovered using our ECM proteomic pipeline, was validated by immunohistochemistry (IHC) of "Tumor" and "Matched Normal" tissues, obtained from an independent cohort of LSCC patients. This integrated workflow provided novel insights into ECM remodeling during CIAC progression, and identified potential biomarker signatures and future therapeutic targets.


Assuntos
Carcinoma de Células Escamosas , Proteômica , Humanos , Matriz Extracelular/metabolismo , Pulmão/metabolismo , Carcinoma de Células Escamosas/patologia , Inflamação/metabolismo , Proteínas da Matriz Extracelular/metabolismo
5.
J Nucl Med ; 64(1): 137-144, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35981900

RESUMO

For the past several decades, chimeric antigen receptor T-cell therapies have shown promise in the treatment of cancers. These treatments would greatly benefit from companion imaging biomarkers to follow the trafficking of T cells in vivo. Methods: Using synthetic biology, we engineered T cells with a chimeric receptor synthetic intramembrane proteolysis receptor (SNIPR) that induces overexpression of an exogenous reporter gene cassette on recognition of specific tumor markers. We then applied a SNIPR-based PET reporter system to 2 cancer-relevant antigens, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII), commonly expressed in breast and glial tumors, respectively. Results: Antigen-specific reporter induction of the SNIPR PET T cells was confirmed in vitro using green fluorescent protein fluorescence, luciferase luminescence, and the HSV-TK PET reporter with 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG). T cells associated with their target antigens were successfully imaged using PET in dual-xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII- animal models, with more than 10-fold higher [18F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. Conclusion: The main innovation found in this work was PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.


Assuntos
Neoplasias da Mama , Glioblastoma , Animais , Humanos , Feminino , Linfócitos T , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Tomografia por Emissão de Pósitrons/métodos , Genes Reporter
6.
Nat Aging ; 1(9): 757-759, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-37117630
7.
Nat Rev Cancer ; 20(3): 174-186, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31980749

RESUMO

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.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Biomarcadores , Fibroblastos Associados a Câncer/efeitos dos fármacos , Plasticidade Celular , Ensaios Clínicos como Assunto , Suscetibilidade a Doenças , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Resultado do Tratamento
9.
Biophys J ; 112(4): 736-745, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28256233

RESUMO

Cancer cells within a tumor are heterogeneous and only a small fraction are able to form secondary tumors. Universal biological markers that clearly identify potentially metastatic cells are limited, which complicates isolation and further study. However, using physical rather than biological characteristics, we have identified Mg2+- and Ca2+-mediated differences in adhesion strength between metastatic and nonmetastatic mammary epithelial cell lines, which occur over concentration ranges similar to those found in tumor stroma. Metastatic cells exhibit remarkable heterogeneity in their adhesion strength under stromal-like conditions, unlike their nonmetastatic counterparts, which exhibit Mg2+- and Ca2+-insensitive adhesion. This heterogeneity is the result of increased sensitivity to Mg2+- and Ca2+-mediated focal adhesion disassembly in metastatic cells, rather than changes in integrin expression or focal adhesion phosphorylation. Strongly adherent metastatic cells exhibit less migratory behavior, similar to nonmetastatic cell lines but contrary to the unselected metastatic cell population. Adhesion strength heterogeneity was observed across multiple cancer cell lines as well as isogenically, suggesting that adhesion strength may serve as a general marker of metastatic cells.


Assuntos
Adesão Celular , Metástase Neoplásica , Linhagem Celular Tumoral , Movimento Celular , Adesões Focais , Humanos
11.
Cell Signal ; 28(12): 1923-1932, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27705752

RESUMO

Endogenous Plastic Somatic (ePS) cells isolated from adult human tissues exhibit extensive lineage plasticity in vitro and in vivo. Here we visualize these rare ePS cells in a latent state, i.e. lacking SOX2, OCT3/4 and NANOG (SON) expression, in non-diseased breast specimens through immunohistochemical analysis of previously identified ePS-specific biomarkers (CD73+, EpCAM+ and CD90-). We also report a novel mechanism by which these latent ePS cells acquire SON expression and plasticity in vitro. Four extracellular factors are necessary for the acquisition of SON expression and lineage plasticity in ePS cells: adenosine (which is produced by the 5' ecto-nucleotidase CD73 and activates in turn the PKA-dependent IL6/STAT3 pathway through the adenosine receptor ADORA2b), IL6, FGF2 and ACTIVIN A. Blocking any pathway component renders ePS cells incapable of SON expression and lineage plasticity. Notably, hESCs do not use adenosine or IL6 nor they express CD73 or ADORA2b and inhibition of adenosine signaling does not ablate their plasticity. Therefore, the data presented here delineate novel circuitry and physiological signals for accessing SON expression in rare, undifferentiated human cells.


Assuntos
5'-Nucleotidase/metabolismo , Plasticidade Celular , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Adenosina/metabolismo , Adulto , Animais , Comunicação Autócrina , Biomarcadores/metabolismo , Mama/metabolismo , Diferenciação Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Alimentadoras/citologia , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Proteínas Ligadas por GPI/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Camundongos , Receptor A2B de Adenosina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Antígenos Thy-1/metabolismo
12.
Genes Dev ; 30(9): 1002-19, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27151975

RESUMO

The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.


Assuntos
Carcinoma/patologia , Fibroblastos/patologia , Animais , Carcinoma/fisiopatologia , Carcinoma/terapia , Progressão da Doença , Humanos
13.
Breast Cancer Res Treat ; 157(2): 351-361, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27146587

RESUMO

Among women diagnosed with ductal carcinoma in situ (DCIS), we identified factors associated with local invasive cancer (LIC) and regional/metastatic invasive cancer (RMIC) and provide 10-year risks based on clinically relevant factors. We created a retrospective, population-based cohort of 1492 women with an initial diagnosis of DCIS (1983-1996) treated by lumpectomy alone. Histological and molecular markers (Ki67, ER, PR, COX-2, p16, ERBB2) were collected on DCIS cases with a subsequent tumor (DCIS, LIC, or RMIC) and a subsample of frequency-matched controls without subsequent tumors. Competing risks methods were used to identify factors associated with LIC and RMIC and cumulative incidence methods to estimate 10-year risks for combinations of factors. Median follow-up time was 12.6 years (range 0.5-29.5 years). The overall 10-year risk of LIC (11.9 %) was higher than for RMIC (3.8 %). About half of women with initial DCIS lesions are detected by mammography and p16 negative and have a 10-year risk of LIC of 6.2 % (95 % CI 5.8-6.8 %) and RMIC of 1.2 % (95 % CI 1.1-1.3 %). Premenopausal women whose DCIS lesion was p16 positive or p16 negative and detected by palpation had high 10-year risk of LIC of 23.0 % (95 % CI 19.3-27.4 %). Ten-year risk of RMIC was highest at 22.5 % (95 % CI 13.8-48.1 %) for those positive for p16, COX-2, and ERRB2, and negative for ER, but prevalence of this group is low at 3 %. Ten-year risk of LIC and RMIC is low for the majority diagnosed with DCIS. Combinations of molecular markers and method of detection of initial DCIS lesion can differentiate women at low and high risk of LIC and RMIC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/cirurgia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Feminino , Humanos , Mamografia , Mastectomia Segmentar , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
14.
Sci Rep ; 5: 15153, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26472542

RESUMO

3D tissue culture models are utilized to study breast cancer and other pathologies because they better capture the complexity of in vivo tissue architecture compared to 2D models. However, to mimic the in vivo environment, the mechanics and geometry of the ECM must also be considered. Here, we studied the mechanical environment created in two 3D models, the overlay protocol (OP) and embedded protocol (EP). Mammary epithelial acini features were compared using OP or EP under conditions known to alter acinus organization, i.e. collagen crosslinking and/or ErbB2 receptor activation. Finite element analysis and active microrheology demonstrated that OP creates a physically asymmetric environment with non-uniform mechanical stresses in radial and circumferential directions. Further contrasting with EP, acini in OP displayed cooperation between ErbB2 signalling and matrix crosslinking. These differences in acini phenotype observed between OP and EP highlight the functional impact of physical symmetry in 3D tissue culture models.


Assuntos
Modelos Biológicos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular , Colágeno/química , Combinação de Medicamentos , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Feminino , Análise de Elementos Finitos , Humanos , Laminina/química , Pinças Ópticas , Fenótipo , Proteoglicanas/química , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo , Reologia , Transdução de Sinais , Estresse Mecânico
15.
Org Biomol Chem ; 13(45): 11078-86, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26400105

RESUMO

Cyclooxygenases (COXs) are enzymes that play a vital role in the inflammatory cascade through the generation of prostaglandins. Their over-expression has been implicated in numerous diseases. In particular, over-expression of COX-2 has been shown to be a predictive biomarker for progression of pre-malignant lesions towards invasive cancer in various tissues. This makes the early detection of COX-2 expressing lesions of high clinical relevance. Herein we describe the development of the first self-immolating trigger which targets COXs. We incorporated our trigger design into 2 activatable fluorogenic probes and demonstrated COX-specific activation in vitro. Experimental data revealed probe activation was likely caused by solvent-exposed amino acids on the surface of the COXs. Overall, the probes reported here mark the first step towards developing self-immolating imaging/therapeutic agents targeted to specific COXs.


Assuntos
Aspirina/análogos & derivados , Aspirina/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Animais , Linhagem Celular , Ciclo-Oxigenase 1/análise , Ciclo-Oxigenase 2/análise , Humanos , Camundongos , Modelos Moleculares , Imagem Óptica , Ovinos , Espectrometria de Fluorescência , Suínos
16.
Nat Commun ; 6: 6351, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25690954

RESUMO

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.


Assuntos
Mama/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Mama/citologia , Ciclo Celular , Diferenciação Celular , Separação Celular , Cromatina/química , Imunoprecipitação da Cromatina , Ilhas de CpG , Epigenômica , Células Epiteliais/citologia , Éxons , Feminino , Citometria de Fluxo , Genoma Humano , Histonas/química , Humanos , Íntrons , Cariotipagem , MicroRNAs/metabolismo , Análise de Sequência de RNA , Transcrição Gênica
17.
Nat Commun ; 6: 6363, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25691127

RESUMO

The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage.


Assuntos
Metilação de DNA , Regulação da Expressão Gênica , Genoma Humano , Sintenia , Animais , Epigenômica , Evolução Molecular , Código das Histonas , Humanos , Camundongos
18.
Nat Commun ; 5: 5442, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25421844

RESUMO

Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts, to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network.


Assuntos
Ectoderma/metabolismo , Epigênese Genética , Redes Reguladoras de Genes , Diferenciação Celular , Células Cultivadas , Metilação de DNA , Ectoderma/citologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Melanócitos/citologia , Melanócitos/metabolismo , Regiões Promotoras Genéticas , Especificidade da Espécie
19.
Interface Focus ; 4(4): 20140028, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25097749

RESUMO

Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression.

20.
Interface Focus ; 4(4): 20140037, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25097751

RESUMO

Failure to understand evolutionary dynamics has been hypothesized as limiting our ability to control biological systems. An increasing awareness of similarities between macroscopic ecosystems and cellular tissues has inspired optimism that game theory will provide insights into the progression and control of cancer. To realize this potential, the ability to compare game theoretic models and experimental measurements of population dynamics should be broadly disseminated. In this tutorial, we present an analysis method that can be used to train parameters in game theoretic dynamics equations, used to validate the resulting equations, and used to make predictions to challenge these equations and to design treatment strategies. The data analysis techniques in this tutorial are adapted from the analysis of reaction kinetics using the method of initial rates taught in undergraduate general chemistry courses. Reliance on computer programming is avoided to encourage the adoption of these methods as routine bench activities.

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