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BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer that disproportionately affects Black women and contributes to racial disparities in breast cancer mortality. Prior research has suggested that neighborhood effects may contribute to this disparity beyond individual risk factors. METHODS: The sample included a cohort of 3316 breast cancer cases diagnosed between 2012 and 2020 in New Castle County, Delaware, a geographic region of the US with elevated rates of TNBC. Multilevel methods and geospatial mapping evaluated whether the race, income, and race/income versions of the neighborhood Index of Concentration at the Extremes (ICE) metric could efficiently identify census tracts (CT) with higher odds of TNBC relative to other forms of invasive breast cancer. Odds ratios (OR) and 95% confidence intervals (CI) were reported; p-values < 0.05 were significant. Additional analyses examined area-level differences in exposure to metabolic risk factors, including unhealthy alcohol use and obesity. RESULTS: The ICE-Race, -Income-, and Race/Income metrics were each associated with greater census tract odds of TNBC on a bivariate basis. However, only ICE-Race was significantly associated with higher odds of TNBC after adjustment for patient-level age and race (most disadvantaged CT: OR = 2.09; 95% CI 1.40-3.13), providing support for neighborhood effects. Higher counts of alcohol and fast-food retailers, and correspondingly higher rates of unhealthy alcohol use and obesity, were observed in CTs that were classified into the most disadvantaged ICE-Race quintile and had the highest odds of TNBC. CONCLUSION: The use of ICE can facilitate the monitoring of cancer inequities and advance the study of racial disparities in breast cancer.
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Neoplasias de Mama Triplo Negativas , Mama , Feminino , Humanos , Obesidade , Características de Residência , Fatores Socioeconômicos , Neoplasias de Mama Triplo Negativas/epidemiologiaRESUMO
BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC. METHODS: We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. RESULTS: Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. CONCLUSIONS: These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.
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Neoplasias de Mama Triplo Negativas , Formação de Anticorpos , Comunicação Celular , Linhagem Celular Tumoral , Humanos , Switching de Imunoglobulina , Imunoglobulina G/metabolismo , Interleucina-10/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Regulação para CimaRESUMO
Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6-7-6 tricyclic core structure of these interesting synthetic targets based on a two-step enolate alkylation and ring-closing metathesis reaction sequence.
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Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able to repopulate the tumor. The Hedgehog (HH) signaling pathway has been shown to regulate the proliferation and survival of breast cancer stem cells, and has been shown to promote resistance to chemotherapy through the activation of multi-drug resistance and pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4-24 h after DOC treatment. This activation had little effect on the bulk of the tumor cell population as inhibition of HH signaling failed to increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemness markers as well as mammosphere formation were observed after treatment with DOC suggesting an increase in the breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced by DOC treatment does not have a chemosensitizing effect on the heterogeneous tumor population, but may be required for survival and expansion of breast cancer stem cells after chemotherapy.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteínas Hedgehog/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Docetaxel , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Despite similar incidence rates among Black and White women, breast cancer mortality rates are 40% higher among Black women. More than half of the racial difference in breast cancer mortality can be attributed to triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that disproportionately affects Black women. Recent research has implicated neighborhood conditions in the etiology of TNBC. This study investigated the relationship between cumulative neighborhood-level exposures and TNBC risk. METHODS: This single-institution retrospective study was conducted on a cohort of 3316 breast cancer cases from New Castle County, Delaware (from 2012 to 2020), an area of the country with elevated TNBC rates. Cases were stratified into TNBC and "Non-TNBC" diagnosis and geocoded by residential address. Neighborhood exposures included census tract-level measures of unhealthy alcohol use, metabolic dysfunction, breastfeeding, and environmental hazards. An overall cumulative risk score was calculated based on tract-level exposures. RESULTS: Univariate analyses showed each tract-level exposure was associated with greater TNBC odds. In multivariate analyses that controlled for patient-level race and age, tract-level exposures were not associated with TNBC odds. However, in a second multivariate model that included patient-level variables and considered tract-level risk factors as a cumulative exposure risk score, each one unit increase in cumulative exposure was significantly associated with a 10% increase in TNBC odds. Higher cumulative exposure risk scores were found in census tracts with relatively high proportions of Black residents. CONCLUSIONS: Cumulative exposure to neighborhood-level risk factors that disproportionately affect Black communities was associated with greater TNBC risk.
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População Negra , Características de Residência , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , População Negra/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 (225Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on 225Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in 225Ac source production, dosimetry modeling, and current clinical studies.
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Braquiterapia , Neoplasias , Humanos , Braquiterapia/métodos , Neoplasias/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Actínio/uso terapêuticoRESUMO
Activation of hedgehog (HH) pathway signaling is observed in many tumors. Due to a feedback loop, the HH receptor Patched (PTCH-1) is overexpressed in tumors with activated HH signaling. Therefore, we sought to radiolabel the PTCH-1 ligand sonic (SHH) for detection of cancer cells with canonical HH activity. Receptor binding of ¹³¹I-SHH was increased in cell lines with high HH pathway activation. Our findings also show that PTCH-1 receptor expression is decreased upon treatment with HH signaling inhibitors, and receptor binding of ¹³¹I-SHH is significantly decreased following treatment with cyclopamine. In vivo imaging and biodistribution studies revealed significant accumulation of ¹³¹I-SHH within tumor tissue as compared to normal organs. Tumor-to-muscle ratios were approximately 8 : 1 at 5 hours, while tumor to blood and tumor to bone were 2 : 1 and 5 : 1, respectively. Significant uptake was also observed in liver and gastrointestinal tissue. These studies show that ¹³¹I-SHH is capable of in vivo detection of breast tumors with high HH signaling. We further demonstrate that the hedgehog receptor PTCH-1 is downregulated upon treatment with hedgehog inhibitors. Our data suggests that radiolabeled SHH derivatives may provide a method to determine response to SHH-targeted therapies.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas Hedgehog/metabolismo , Marcação por Isótopo , Transdução de Sinais , Animais , Bioensaio , Western Blotting , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Câmaras gama , Humanos , Radioisótopos do Iodo , Proteínas Oncogênicas/metabolismo , Receptores Patched , Receptor Patched-1 , Ligação Proteica/efeitos dos fármacos , Radiometria , Cintilografia , Ratos , Ratos Endogâmicos F344 , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Transativadores/metabolismo , Alcaloides de Veratrum/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de ZincoRESUMO
BACKGROUND: The NCI requires designated cancer centers to conduct catchment area assessments to guide cancer control and prevention efforts designed to reduce the local cancer burden. We extended and adapted this approach to a community cancer center catchment area with elevated rates of triple-negative breast cancer (TNBC). METHODS: Cancer registry data for 462 TNBC and 2,987 "Not-TNBC" cases diagnosed between 2012 and 2020 at the Helen F. Graham Cancer Center & Research Institute (HFGCCRI), located in New Castle County, Delaware, were geocoded to detect areas of elevated risk (hot spots) and decreased risk (cold spots). Next, electronic health record (EHR) data on obesity and alcohol use disorder (AUD) and catchment area measures of fast-food and alcohol retailers were used to assess for spatial relationships between TNBC hot spots and potentially modifiable risk factors. RESULTS: Two hot and two cold spots were identified for TNBC within the catchment area. The hot spots accounted for 11% of the catchment area but nearly a third of all TNBC cases. Higher rates of unhealthy alcohol use and obesity were observed within the hot spots. CONCLUSIONS: The use of spatial methods to analyze cancer registry and other secondary data sources can inform cancer control and prevention efforts within community cancer center catchment areas, where limited resources can preclude the collection of new primary data. IMPACT: Targeting community outreach and engagement activities to TNBC hot spots offers the potential to reduce the population-level burden of cancer efficiently and equitably.
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Consumo de Bebidas Alcoólicas/epidemiologia , Área Programática de Saúde , Obesidade/epidemiologia , Neoplasias de Mama Triplo Negativas/epidemiologia , Idoso , Delaware/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Saúde da População , Sistema de Registros , Fatores de RiscoRESUMO
There is no targeted therapy for triple negative breast cancer (TNBC), which presents an aggressive profile and poor prognosis. Recent studies noticed the feasibility of breast cancer stem cells (BCSCs), a small population responsible for tumor initiation and relapse, to become a novel target for TNBC treatments. However, new cell culture supports need to be standardized since traditional two-dimensional (2D) surfaces do not maintain the stemness state of cells. Hence, three-dimensional (3D) scaffolds represent an alternative to study in vitro cell behavior without inducing cell differentiation. In this work, electrospun polycaprolactone scaffolds were used to enrich BCSC subpopulation of MDA-MB-231 and MDA-MB-468 TNBC cells, confirmed by the upregulation of several stemness markers and the existence of an epithelial-to-mesenchymal transition within 3D culture. Moreover, 3D-cultured cells displayed a shift from MAPK to PI3K/AKT/mTOR signaling pathways, accompanied by an enhanced EGFR and HER2 activation, especially at early cell culture times. Lastly, the fatty acid synthase (FASN), a lipogenic enzyme overexpressed in several carcinomas, was found to be hyperactivated in stemness-enriched samples. Its pharmacological inhibition led to stemness diminishment, overcoming the BCSC expansion achieved in 3D culture. Therefore, FASN may represent a novel target for BCSC niche in TNBC samples.
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Purpose: Pro-inflammatory cytokines within the tumor microenvironment, such as IL-6, contribute to the maintenance of stem cells and promote their survival following treatment. The IL-6/STAT3 pathway is a key regulator of genes involved in cancer progression. Activation of STAT3 promotes expansion of cancer stem cells in triple negative breast cancer. Radiation has also been shown to expand cancer stem cell populations and can induce stemness in nonstem cells. However, the role of IL-6/STAT3 in radiation-induced changes in cellular plasticity is unclear.Materials and methods: Expression and secretion of IL-6 from triple-negative breast cancer cell lines SUM159PT and MDA-MB-231 were determined after radiation treatment by real-time PCR and ELISA. Activation of STAT3 after radiation was determined by western blotting. Changes in cellular plasticity induced by radiation were determined by examining ALDEFLUOR activity, gene expression analysis of aldehyde dehydrogenase isoforms and mammosphere forming assays with and without the addition of STAT3 inhibitors. To determine the effect of radiation on nonstem cell populations, experiments were also carried out in ALDEFLUOR sorted cells.Results: Radiation induced an inflammatory response in both cell lines that resulted in activation of STAT3. Additionally, radiation induced a stem-like state as evidenced by an increased activity and expression of the ALDH isoforms ALDH1A1 and ALDH1A3, and increased self-renewal capabilities. Radiation increased ALDH activity and self-renewal in non-stem cell (ALDH-) populations, suggesting radiation-induced cellular reprograming. However, inhibition of STAT3 blocked the radiation-induced stem-like state in both ALDEFLUOR positive and negative populations, and enhanced radiosensitivity.Conclusions: Radiation-induced changes in cellular plasticity are STAT3 dependent and may be a potential target to reduce radioresistance in TNBC and improve treatment outcome.
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Neoplasias da Mama/radioterapia , Plasticidade Celular/efeitos da radiação , Inflamação/fisiopatologia , Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação , Fator de Transcrição STAT3/fisiologia , Aldeído Desidrogenase/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-6/fisiologia , Janus Quinase 2/fisiologia , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos da radiaçãoRESUMO
Resistance to chemotherapy substantially hinders successful glioblastoma (GBM) treatment, contributing to an almost 100% mortality rate. Resistance to the frontline chemotherapy, temozolomide (TMZ), arises from numerous signaling pathways that are deregulated in GBM, including Hedgehog (Hh) signaling. Here, we investigate suppression of Hh signaling as an adjuvant to TMZ using U87-MG and T98G cell lines as in vitro models of GBM. We found that silencing GLI1 with siRNA reduces cell metabolic activity by up to 30% in combination with TMZ and reduces multidrug efflux activity by 2.5-fold. Additionally, pharmacological GLI inhibition modulates nuclear p53 levels and decreases MGMT expression in combination with TMZ. While we surprisingly found that silencing GLI1 does not induce apoptosis in the absence of TMZ co-treatment, we discovered silencing GLI1 without TMZ co-treatment induces senescence as evidenced by a significant 2.3-fold increase in senescence associated ß-galactosidase staining, and this occurs in a loss of PTEN-dependent manner. Finally, we show that GLI inhibition increases apoptosis in glioma stem-like cells by up to 6.8-fold in combination with TMZ, and this reduces the size and number of neurospheres grown from glioma stem-like cells. In aggregate, our data warrant the continued investigation of Hh pathway inhibitors as adjuvants to TMZ chemotherapy and highlight the importance of identifying signaling pathways that determine whether co-treatment will be successful.
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In addition to inducing lethal DNA damage in tumor and stromal cells, radiation can alter the interactions of tumor cells with their microenvironment. Recent technological advances in planning and delivery of external beam radiotherapy have allowed delivery of larger doses per fraction (hypofractionation) while minimizing dose to normal tissues with higher precision. The effects of radiation on the tumor microenvironment vary with dose and fractionation schedule. In this review, we summarize the effects of conventional and hypofractionated radiation regimens on the immune system and tumor stroma. We discuss how these interactions may provide therapeutic benefit in combination with targeted therapies. Understanding the differential effects of radiation dose and fractionation can have implications for choice of combination therapies.
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PURPOSE: Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown. EXPERIMENTAL DESIGN: The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation. RESULTS: We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells. CONCLUSIONS: These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.
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Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Proteínas Hedgehog/metabolismo , Tolerância a Radiação/fisiologia , Animais , Antineoplásicos/uso terapêutico , Western Blotting , Proliferação de Células , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Interferência de RNA , Radioterapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hedgehog (HH) and Wnt pathway activation have been implicated in poor prognosis of breast cancer. Crosstalk between these two pathways has been demonstrated to be important in breast cancer progression, however the association between these two pathways and breast cancer survival rate is unknown. The present study comprised a cohort of 36 patients with triple negative breast cancer (TNBC) to investigate co-activation of HH and canonical Wnt pathway in association to patient outcome. All patients had varying degrees of cytoplasmic sonic HH and glioma-associated oncogene homolog (Gli)-1 staining, which positively correlated with tumor stage. Nuclear ß-catenin was additionally correlated to tumor stage. A significant association was observed between nuclear Gli-1 and nuclear ß-catenin. Co-activation of HH and Wnt pathways was associated with poorer prognosis in TNBC patients resulting in a greater risk of early recurrence and decreased overall survival rate compared with patients with only one pathway activated. Therefore, the combined activation status of the HH and Wnt pathways may be a useful prognostic marker for TNBC patients at risk for early recurrence.
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The influence of tumor infiltrating lymphocytes on tumor growth and response to therapy is becoming increasingly apparent. While much work has focused on the role of T cell responses in anti-tumor immunity, the role of B cells in solid tumors is much less understood. Tumor infiltrating B cells have been found in a variety of solid tumors, including breast, ovarian, prostate, melanoma, and colorectal cancer. The function of B cells in solid tumors is controversial, with many studies reporting a pro-tumor effect, while other studies demonstrate a role for B cells in the anti-tumor immune response. In this review, we discuss the prognostic ability of B cells in solid tumors as well as the mechanisms by which B cells can either promote or suppress anti-tumor immunity. Additionally, we review current therapeutic strategies that may target both pro- and anti-tumor B cells.
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Linfócitos B/imunologia , Neoplasias/imunologia , Humanos , Microambiente TumoralRESUMO
Obesity rates within the United States are on the rise. Obesity is a known risk factor for various diseases, including cancer. Numerous studies have linked obesity to the incidence and treatment outcomes of breast cancer. However, the risk of obesity may vary between breast cancer subtypes and different racial or age groups. In this article, we review the literature regarding the impact of obesity on incidence and response for different subtypes of breast cancer within different population groups.
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We previously showed that the human AKNA gene encodes an AT-hook transcription factor that regulates the expression of costimulatory cell surface molecules on lymphocytes. However, AKNA cDNA probes hybridize with multiple transcripts, suggesting either the existence of other homologous genes or a complex regulation operating on a single gene. Here we report evidence for the latter, as we find that AKNA is encoded by a single gene that spans a 61-kb locus of 24 exons on the fragile FRA9E region of human chromosome 9q32. This gene gives rise to at least nine distinct transcripts, most of which are expressed in a tissue-specific manner in lymphoid organs. Many of the AKNA transcripts originate from alternative splicing; others appear to derive from differential polyadenylation and promoter usage. The alternative AKNA transcripts are predicted to encode overlapping protein isoforms, some of which (p70 and p100) are readily detectable using a polyclonal anti-AKNA antisera that we generated. We also find that AKNA PEST-dependent cleavage into p50 polypeptides is targeted to mature B cells and appears to be required for CD40 upregulation. The unusual capacity of the AKNA gene to generate multiple transcripts and proteins may reflect its functional diversity, and it may also provide a fail-safe mechanism that preserves AKNA expression.
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Processamento Alternativo , Poliadenilação , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Fatores de Transcrição/genética , Linfócitos B/metabolismo , Western Blotting , Antígenos CD40/metabolismo , Núcleo Celular/metabolismo , Cromossomos Humanos Par 9 , Proteínas de Ligação a DNA , Ensaio de Desvio de Mobilidade Eletroforética , Éxons , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Tecido Linfoide/metabolismo , Proteínas Nucleares , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Mapeamento por Restrição , Linfócitos T/metabolismoRESUMO
The relationship between wound healing and cancer has long been recognized. The mechanisms that regulate wound healing have been shown to promote transformation and growth of malignant cells. In addition, chronic inflammation has been associated with malignant transformation in many tissues. Recently, pathways involved in inflammation and wound healing have been reported to enhance cancer stem cell (CSC) populations. These cells, which are highly resistant to current treatments, are capable of repopulating the tumor after treatment, causing local and systemic recurrences. In this review, we highlight proinflammatory cytokines and developmental pathways involved in tissue repair, whose deregulation in the tumor microenvironment may promote growth and survival of CSCs. We propose that the addition of anti-inflammatory agents to current treatment regimens may slow the growth of CSCs and improve therapeutic outcomes.
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Triple Negative Breast Cancer (TNBC) is characterized as a lack of expression of the hormonal receptors, estrogen and progesterone, and Human epidermal growth factor receptor 2 (HER2) and as such is unresponsive to current targeted therapy. Resistance of breast cancers to treatment is thought to be due to a sub-population of tumor cells called Breast Cancer Stem Cells (BCSCs) and contributes to poor prognosis and increased risk of recurrence. Previously, we have shown that hedgehog activation is induced by chemotherapy and promotes expansion of a stem-like population in breast cancer cell lines. In addition, chemotherapy can induce an inflammatory response and inflammatory factors can lead to activation of Hedgehog (HH) at sites of tissue injury. Therefore, we wanted to investigate how chemotherapy altered hedgehog signaling and correlated with the release of inflammatory cytokines in a mouse model of breast cancer. Patient derived triple negative breast tumor bearing mice were treated with weekly doses of docetaxel. Following treatment, tumor volume decreased reaching a nadir around 15 days after the start of treatment and increased back to pre-treatment size 35-39 days post treatment. Immunohistochemical staining of mice tumors revealed that Sonic hedgehog and nuclear Gli-1 expression transiently increased following docetaxel treatment, reached peak expression at day 8, and subsequently decreased to almost pre-treatment levels following regrowth of the tumor. Similarly, Interleukin 6 (IL-6) and Interleukin 8 (IL-8) expression transiently increased, peaked around day 8, and decreased upon tumor regrowth, however, remained above pre-treatment levels. Expression of the stem cell marker ALDH1A3 proceeded activation of hedgehog signaling and expression of inflammatory cytokines, increasing around day 15 post treatment and continued to be elevated during tumor regrowth. Thus, chemotherapy treatment resulted in activation of the hedgehog pathway and release of inflammatory cytokines leading to long-term expansion of ALDH1A3 positive stem cells, which can contribute to the regrowth of the tumor and promote resistance to treatment.
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High tumor hedgehog expression is correlated with poor prognosis in invasive ductal carcinoma. Peptides which bind the patched receptor have recently been reported to have a growth inhibitory effect in tumors with activated hedgehog signaling. We sought to examine growth inhibition with these peptides in breast cancer cells and use these peptides as molecular imaging probes to follow changes in hedgehog expression after chemotherapy. Significant growth inhibition was observed in breast cancer cell lines treated with PTCH-blocking peptides. Significant in vitro uptake was observed with both FITC- and (99m)Tc-EC-peptide conjugates. In vivo imaging studies displayed greater accumulation of (99m)Tc-labeled peptides within tumors as compared to adjacent muscle tissue. Patched receptor expression increased after treatment and this correlated with an increase in tumor radiotracer uptake. These studies suggest that peptides which bind the sonic hedgehog docking site in patched receptor correlate with patched expression and can be used to image patched in vivo. Further, our data suggest that radiolabeled peptides may enable us to examine the activity of the hedgehog signaling pathway and to evaluate response to anti-cancer therapies.