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1.
Cell ; 174(1): 72-87.e32, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29861175

RESUMO

Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.


Assuntos
Hipóxia Celular , Relógios Circadianos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Aminoácidos Dicarboxílicos/farmacologia , Animais , Proteínas CLOCK/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Relógios Circadianos/efeitos dos fármacos , Meios de Cultura/química , Fatores de Iniciação em Eucariotos , Concentração de Íons de Hidrogênio , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Proteína 2 do Complexo Esclerose Tuberosa/genética
2.
Semin Cancer Biol ; 102-103: 17-24, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38969311

RESUMO

Oxygen played a pivotal role in the evolution of multicellularity during the Cambrian Explosion. Not surprisingly, responses to fluctuating oxygen concentrations are integral to the evolution of cancer-a disease characterized by the breakdown of multicellularity. Poorly organized tumor vasculature results in chaotic patterns of blood flow characterized by large spatial and temporal variations in intra-tumoral oxygen concentrations. Hypoxia-inducible growth factor (HIF-1) plays a pivotal role in enabling cells to adapt, metabolize, and proliferate in low oxygen conditions. HIF-1 is often constitutively activated in cancers, underscoring its importance in cancer progression. Here, we argue that the phenotypic changes mediated by HIF-1, in addition to adapting the cancer cells to their local environment, also "pre-adapt" them for proliferation at distant, metastatic sites. HIF-1-mediated adaptations include a metabolic shift towards anaerobic respiration or glycolysis, activation of cell survival mechanisms like phenotypic plasticity and epigenetic reprogramming, and formation of tumor vasculature through angiogenesis. Hypoxia induced epigenetic reprogramming can trigger epithelial to mesenchymal transition in cancer cells-the first step in the metastatic cascade. Highly glycolytic cells facilitate local invasion by acidifying the tumor microenvironment. New blood vessels, formed due to angiogenesis, provide cancer cells a conduit to the circulatory system. Moreover, survival mechanisms acquired by cancer cells in the primary site allow them to remodel tissue at the metastatic site generating tumor promoting microenvironment. Thus, hypoxia in the primary tumor promoted adaptations conducive to all stages of the metastatic cascade from the initial escape entry into a blood vessel, intravascular survival, extravasation into distant tissues, and establishment of secondary tumors.

3.
Br J Cancer ; 124(2): 455-465, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33024265

RESUMO

BACKGROUND: Cancer progression is governed by evolutionary dynamics in both the tumour population and its host. Since cancers die with the host, each new population of cancer cells must reinvent strategies to overcome the host's heritable defences. In contrast, host species evolve defence strategies over generations if tumour development limits procreation. METHODS: We investigate this "evolutionary arms race" through intentional breeding of immunodeficient SCID and immunocompetent Black/6 mice to evolve increased tumour suppression. Over 10 generations, we injected Lewis lung mouse carcinoma cells [LL/2-Luc-M38] and selectively bred the two individuals with the slowest tumour growth at day 11. Their male progeny were hosts in the subsequent round. RESULTS: The evolved SCID mice suppressed tumour growth through biomechanical restriction from increased mesenchymal proliferation, and the evolved Black/6 mice suppressed tumour growth by increasing immune-mediated killing of cancer cells. However, transcriptomic changes of multicellular tissue organisation and function genes allowed LL/2-Luc-M38 cells to adapt through increased matrix remodelling in SCID mice, and reduced angiogenesis, increased energy utilisation and accelerated proliferation in Black/6 mice. CONCLUSION: Host species can rapidly evolve both immunologic and non-immunologic tumour defences. However, cancer cell plasticity allows effective phenotypic and population-based counter strategies.


Assuntos
Adaptação Fisiológica/fisiologia , Evolução Biológica , Carcinoma Pulmonar de Lewis , Plasticidade Celular/fisiologia , Resistência à Doença/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID
4.
Cancer Metastasis Rev ; 38(1-2): 149-155, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30806853

RESUMO

The extracellular pH of solid tumors is unequivocally acidic due to a combination of high rates of lactic acid production (a consequence of fermentative glycolytic metabolism) and poor perfusion. This has been documented by us and others in a wide variety of solid tumor models, primarily using magnetic resonance spectroscopic imaging (MRSI). This acidity contributes to tumor progression by inducing genome instability, promoting local invasion and metastases, inhibiting anti-tumor immunity, and conferring resistance to chemo- and radio-therapies. Systemic buffer therapies can neutralize tumor acidity and has been shown to inhibit local invasion and metastasis and improve immune surveillance in a variety of cancer model systems. This review will revisit the causes and consequences of acidosis by summarizing strategies used by cancer cells to adapt to acidosis, and how this acidity associated with carcinogenesis, metastasis, and immune function. Finally, this review will discuss how neutralization of acidity can be used to inhibit carcinogenesis and metastasis and improve anti-cancer immunotherapy.


Assuntos
Acidose/metabolismo , Neoplasias/metabolismo , Bicarbonato de Sódio/farmacologia , Acidose/tratamento farmacológico , Acidose/imunologia , Animais , Soluções Tampão , Humanos , Concentração de Íons de Hidrogênio , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
6.
Br J Cancer ; 121(7): 556-566, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31417189

RESUMO

BACKGROUND: Tumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. We hypothesise that acidity, independent from lactate, can augment the pro-tumour phenotype of macrophages. METHODS: We analysed publicly available data of human prostate cancer for linear correlation between macrophage markers and glycolysis genes. We used zwitterionic buffers to adjust the pH in series of in vitro experiments. We then utilised subcutaneous and transgenic tumour models developed in C57BL/6 mice as well as computer simulations to correlate tumour progression with macrophage infiltration and to delineate role of acidity. RESULTS: Activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralising intratumoural acidity reduced the pro-tumour phenotype of macrophages, while also decreasing tumour incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modelling shows that acid-resistant macrophages can limit tumour progression. CONCLUSIONS: This study suggests that tumour acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.


Assuntos
Progressão da Doença , Ativação de Macrófagos , Macrófagos/fisiologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Bicarbonatos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Citocinas/metabolismo , Espaço Extracelular/metabolismo , Expressão Gênica , Glucose/metabolismo , Glicólise/genética , Humanos , Concentração de Íons de Hidrogênio , Interleucina-4/metabolismo , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Teóricos , Invasividade Neoplásica , Fenótipo , Distribuição Aleatória , Microambiente Tumoral
7.
Immunology ; 154(3): 354-362, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29485185

RESUMO

Due to imbalances between vascularity and cellular growth patterns, the tumour microenvironment harbours multiple metabolic stressors including hypoxia and acidosis, which have significant influences on remodelling both tumour and peritumoral tissues. These stressors are also immunosuppressive and can contribute to escape from immune surveillance. Understanding these effects and characterizing the pathways involved can identify new targets for therapy and may redefine our understanding of traditional anti-tumour therapies. In this review, the effects of hypoxia and acidosis on tumour immunity will be summarized, and how modulating these parameters and their sequelae can be a useful tool for future therapeutic interventions is discussed.


Assuntos
Acidose/imunologia , Acidose/metabolismo , Hipóxia/imunologia , Hipóxia/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Microambiente Tumoral , Acidose/terapia , Animais , Humanos , Hipóxia/terapia , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tolerância Imunológica , Vigilância Imunológica , Imunoterapia , Neoplasias/patologia , Neoplasias/terapia , Evasão Tumoral , Microambiente Tumoral/imunologia
8.
Int J Cancer ; 140(6): 1331-1345, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-27888521

RESUMO

The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hr, H+ -MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+ -MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5 and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+ -MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS.


Assuntos
Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , Células-Tronco Mesenquimais/fisiologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Osteossarcoma/patologia , Células Estromais/fisiologia , Microambiente Tumoral , Animais , Neoplasias Ósseas/veterinária , Linhagem Celular Tumoral , Técnicas de Cocultura , Meios de Cultivo Condicionados , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , Doenças do Cão/patologia , Cães , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/veterinária , Comunicação Parácrina , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Transdução de Sinais
9.
iScience ; 27(1): 108593, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38174318

RESUMO

Gene expression change is a dominant mode of evolution. Mutations, however, can affect gene expression in multiple cell types. Therefore, gene expression evolution in one cell type can lead to similar gene expression changes in another cell type. Here, we test this hypothesis by investigating dermal skin fibroblasts (SFs) and uterine endometrial stromal fibroblasts (ESFs). The comparative dataset consists of transcriptomes from cultured SF and ESF of nine mammalian species. We find that evolutionary changes in gene expression in SF and ESF are highly correlated. The experimental dataset derives from a SCID mouse strain selected for slow cancer growth leading to substantial gene expression changes in SFs. We compared the gene expression profiles of SF with that of ESF and found a significant correlation between them. We discuss the implications of these findings for the evolutionary correlation between placental invasiveness and vulnerability to metastatic cancer.

10.
Biomedicines ; 12(2)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38398062

RESUMO

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

11.
PLoS One ; 18(10): e0292492, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37816047

RESUMO

INTRODUCTION: Volatile and intravenous anesthetics may worsen oncologic outcomes in basic science animal models. These effects may be related to suppressed innate and adaptive immunity, decreased immunosurveillance, and disrupted cellular signaling. We hypothesized that anesthetics would promote lung tumor growth via altered immune function in a murine model and tested this using an immunological control group of immunodeficient mice. METHODS: Lewis lung carcinoma cells were injected via tail vein into C57BL/6 immunocompetent and NSG immunodeficient mice during exposure to isoflurane and ketamine versus controls without anesthesia. Mice were imaged on days 0, 3, 10, and 14 post-tumor cell injection. On day 14, mice were euthanized and organs fixed for metastasis quantification and immunohistochemistry staining. We compared growth of tumors measured from bioluminescent imaging and tumor metastasis in ex vivo bioluminescent imaging of lung and liver. RESULTS: Metastases were significantly greater for immunocompromised NSG mice than immunocompetent C57BL/6 mice over the 14-day experiment (partial η2 = 0.67, 95% CI = 0.54, 0.76). Among immunocompetent mice, metastases were greatest for mice receiving ketamine, intermediate for those receiving isoflurane, and least for control mice (partial η2 = 0.88, 95% CI = 0.82, 0.91). In immunocompetent mice, significantly decreased T lymphocyte (partial η2 = 0.83, 95% CI = 0.29, 0.93) and monocyte (partial η2 = 0.90, 95% CI = 0.52, 0.96) infiltration was observed in anesthetic-treated mice versus controls. CONCLUSIONS: The immune system appears central to the pro-metastatic effects of isoflurane and ketamine in a murine model, with decreased T lymphocytes and monocytes likely playing a role.


Assuntos
Anestésicos Inalatórios , Anestésicos , Isoflurano , Ketamina , Camundongos , Animais , Isoflurano/efeitos adversos , Ketamina/farmacologia , Modelos Animais de Doenças , Xilazina/farmacologia , Camundongos Endogâmicos C57BL , Anestésicos/farmacologia , Imunidade , Anestésicos Inalatórios/efeitos adversos
12.
Contrast Media Mol Imaging ; 2023: 1944970, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36704211

RESUMO

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups (p=0.16). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration (p < 0.001). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.


Assuntos
Iopamidol , Neoplasias Pancreáticas , Humanos , Meios de Contraste , Concentração de Íons de Hidrogênio , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Microambiente Tumoral
13.
bioRxiv ; 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37693389

RESUMO

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

14.
J Urol ; 188(2): 624-31, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22704445

RESUMO

PURPOSE: Hypoxia and acidosis develop in in situ tumors as cellular expansion increases the diffusion distance of substrates and metabolites from blood vessels deep to the basement membrane. Prior studies of breast and cervical cancer revealed that cellular adaptation to microenvironmental hypoxia and acidosis is associated with the transition from in situ to invasive cancer. We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer. MATERIALS AND METHODS: A total of 37 C57BL/6 TRAMP mice were randomized to a control group or to 1 of 4 treatment groups. In the latter groups 200 mM sodium bicarbonate were added to drinking water starting between ages 4 and 10 weeks. RESULTS: In all 18 controls prostate cancer developed that was visible on 3-dimensional ultrasound at a mean age of 13 weeks. They died within 52 weeks (median 37). When sodium bicarbonate therapy commenced before age 6 weeks in 10 mice, all reached senescence (age 76 weeks) without radiographic evidence of prostate cancer. Histological sections of the prostates in this cohort showed hyperplasia but no cancer in 70% of mice and minimal well differentiated cancer in the remainder. When therapy commenced after age 6 weeks in 9 mice, prostate cancer development was no different from that in controls. CONCLUSIONS: Immunohistochemical staining for carbonic anhydrase 9 in regions of ductal hyperplasia showed increased expression in controls vs the early treatment group. Regional pH perturbation in in situ tumors may be a simple, inexpensive and effective cancer prevention strategy.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Hipóxia Celular/fisiologia , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Neoplasias da Próstata/patologia , Bicarbonato de Sódio/farmacologia , Equilíbrio Ácido-Base/efeitos dos fármacos , Adaptação Fisiológica/fisiologia , Animais , Soluções Tampão , Hipóxia Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Invasividade Neoplásica/patologia , Transplante de Neoplasias , Fenótipo , Próstata/patologia , Hiperplasia Prostática/patologia , Transplante Heterólogo
15.
Front Oncol ; 12: 981718, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452492

RESUMO

"Dysregulated" metabolism is a characteristic of the cancer cell phenotype. This includes persistent use of glycolytic metabolism in normoxic environments (Warburg effect) leading to increased acid production and accumulation of protons in the interstitial space. Although often thought to be disordered, altered cancer metabolism is the outcome of intense Darwinian selection and, thus, must have evolved to maximize cancer cell fitness. In an evolutionary context, cancer-induced acidification of the microenvironment represents a niche construction strategy to promote proliferation. Ecological advantages conferred on the cancer population included remodeling of the extracellular matrix to promote local invasion, suppression of potential competitive proliferation of fibroblasts, and suppression of host immune response. Preclinical data demonstrates that increasing the serum buffering capacity (through, for example, oral sodium bicarbonate and TRIS) can neutralize the acidic tumor microenvironment with inhibition local invasion and proliferation which can be synergistic with the effects of chemotherapy and immunotherapy agents. Here, we describe the proton dynamics in cancer and their influence on tumor progression and metastasis. Additionally, we will discuss targeting the tumor acidosis with alkalizing agents including our bicarbonate clinical trial results. Clinical Trial Registration: clinicaltrials.gov, identifier NCT01350583, NCT01198821 and NCT01846429.

16.
Math Biosci ; 352: 108909, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36108797

RESUMO

Clinical cancers are typically spatially and temporally heterogeneous, containing multiple microenvironmental habitats and diverse phenotypes and/or genotypes, which can interact through resource competition and direct or indirect interference. A common intratumoral evolutionary pathway, probably initiated as adaptation to hypoxia, leads to the "Warburg phenotype" which maintains high glycolytic rates and acid production, even in normoxic conditions. Since individual cancer cells are the unit of Darwinian selection, intraspecific competition dominates intratumoral evolution. Thus, elements of the Warburg phenotype become key "strategies" in competition with cancer cell populations that retain the metabolism of the parental normal cells. Here we model the complex interactions of cell populations with Warburg and parental phenotypes as they compete for access to vasculature, while subject to direct interference by Warburg-related acidosis. In this competitive environment, vasculature delivers nutrients, removes acid and necrotic detritus, and responds to signaling molecules (VEGF and TNF-α). The model is built in a nested fashion and growth parameters are derived from monolayer, spheroid, and xenograft experiments on prostate cancer. The resulting model of in vivo tumor growth reaches a steady state, displaying linear growth and coexistence of both glycolytic and parental phenotypes consistent with experimental observations. The model predicts that increasing tumor pH sufficiently early can arrest the development of the glycolytic phenotype, while decreasing tumor pH accelerates this evolution and increases VEGF production. The model's predicted dual effects of VEGF blockers in decreasing tumor growth while increasing the glycolytic fraction of tumor cells has potential implications for optimizing angiogenic inhibitors.


Assuntos
Inibidores da Angiogênese , Neoplasias da Próstata , Animais , Glicólise , Humanos , Concentração de Íons de Hidrogênio , Masculino , Fenótipo , Fator de Necrose Tumoral alfa
17.
Carcinogenesis ; 32(8): 1251-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21586513

RESUMO

Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.


Assuntos
Neoplasias da Mama/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Dieta com Restrição de Gorduras , Estearatos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Animais , Western Blotting , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Citometria de Fluxo , Humanos , Fosforilação , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Proteínas ras/genética , Proteínas ras/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo
18.
Sci Rep ; 11(1): 4908, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649456

RESUMO

Tumors are highly dynamic ecosystems in which diverse cancer cell subpopulations compete for space and resources. These complex, often non-linear interactions govern continuous spatial and temporal changes in the size and phenotypic properties of these subpopulations. Because intra-tumoral blood flow is often chaotic, competition for resources may be a critical selection factor in progression and prognosis. Here, we quantify resource competition using 3D spheroid cultures with MDA-MB-231 and MCF-7 breast cancer cells. We hypothesized that MCF-7 cells, which primarily rely on efficient aerobic glucose metabolism, would dominate the population under normal pH and low glucose conditions; and MDA-MB-231 cells, which exhibit high levels of glycolytic metabolism, would dominate under low pH and high glucose conditions. In spheroids with single populations, MCF-7 cells exhibited equal or superior intrinsic growth rates (density-independent measure of success) and carrying capacities (density-dependent measure of success) when compared to MDA-MB-231 cells under all pH and nutrient conditions. Despite these advantages, when grown together, MCF-7 cells do not always outcompete MDA-MB-231 cells. MDA-MB-231 cells outcompete MCF-7 cells in low glucose conditions and coexistence is achieved in low pH conditions. Under all conditions, MDA-MB-231 has a stronger competitive effect (frequency-dependent interaction) on MCF-7 cells than vice-versa. This, and the inability of growth rate or carrying capacity when grown individually to predict the outcome of competition, suggests a reliance on frequency-dependent interactions and the need for competition assays. We frame these results in a game-theoretic (frequency-dependent) model of cancer cell interactions and conclude that competition assays can demonstrate critical density-independent, density-dependent and frequency-dependent interactions that likely contribute to in vivo outcomes.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Comunicação Celular , Feminino , Humanos , Células MCF-7
19.
Nat Commun ; 11(1): 4113, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807791

RESUMO

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfonodos/metabolismo , Animais , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Concentração de Íons de Hidrogênio , Imunoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfofrutoquinase-1/genética , Fosfofrutoquinase-1/metabolismo
20.
Cancer Med ; 6(7): 1720-1729, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28556628

RESUMO

Neutralizing tumor external acidity with oral buffers has proven effective for the prevention and inhibition of metastasis in several cancer mouse models. Solid tumors are highly acidic as a result of high glycolysis combined with an inadequate blood supply. Our prior work has shown that sodium bicarbonate, imidazole, and free-base (but not protonated) lysine are effective in reducing tumor progression and metastasis. However, a concern in translating these results to clinic has been the presence of counter ions and their potential undesirable side effects (e.g., hypernatremia). In this work, we investigate tris(hydroxymethyl)aminomethane, (THAM or Tris), a primary amine with no counter ion, for its effects on metastasis and progression in prostate and pancreatic cancer in vivo models using MRI and bioluminescence imaging. At an ad lib concentration of 200 mmol/L, Tris effectively inhibited metastasis in both models and furthermore led to a decrease in the expression of the major glucose transporter, GLUT-1. Our results also showed that Tris-base buffer (pH 8.4) had no overt toxicity to C3H mice even at higher doses (400 mmol/L). In conclusion, we have developed a novel therapeutic approach to manipulate tumor extracellular pH (pHe) that could be readily adapted to a clinical trial.


Assuntos
Antineoplásicos/farmacologia , Soluções Tampão , Trometamina/farmacologia , Animais , Antineoplásicos/química , Análise Química do Sangue , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Humanos , Concentração de Íons de Hidrogênio , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Imagem Molecular , Metástase Neoplásica , Análise de Sobrevida , Trometamina/química , Carga Tumoral/efeitos dos fármacos , Urinálise , Ensaios Antitumorais Modelo de Xenoenxerto
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