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Liver metastases from gastrointestinal and non-gastrointestinal malignancies remain a major cause of cancer-related mortality and a major clinical challenge. The liver has unique properties that facilitate metastatic expansion, including a complex immune system that evolved to dampen immunity to neoantigens entering the liver from the gut, through the portal circulation. In this review, we describe the unique microenvironment encountered by cancer cells in the liver, focusing on elements of the innate and adaptive immune response that can act as a double-edge sword, contributing to the elimination of cancer cells on the one hand and promoting their survival and growth, on the other. We discuss this microenvironment in a clinical context, particularly for colorectal carcinoma, and highlight how a better understanding of the role of the microenvironment has spurred an intense effort to develop novel and innovative strategies for targeting liver metastatic disease, some of which are currently being tested in the clinic.
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Neoplasias Colorrectales/patología , Inmunidad , Neoplasias Hepáticas/secundario , Microambiente Tumoral , Animales , Neoplasias Colorrectales/inmunología , Humanos , Neoplasias Hepáticas/inmunologíaRESUMEN
The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Animales , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND & AIMS: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. RESULTS: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. LAY SUMMARY: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
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Carcinoma Hepatocelular/metabolismo , Hepatocitos/metabolismo , Interleucina-17/metabolismo , Macrófagos del Hígado/metabolismo , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/metabolismo , Neoplasias Hepáticas/metabolismo , Transducción de Señal/genética , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Etanol/efectos adversos , Eliminación de Gen , Humanos , Cirrosis Hepática/patología , Hepatopatías Alcohólicas/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-17/deficiencia , Receptores de Interleucina-17/genética , TranscriptomaRESUMEN
BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Metástasis de la Neoplasia/patología , HumanosRESUMEN
Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. LM and the female sex are predictors of a poorer response to immunotherapy but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of colorectal carcinoma liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a multiplex cytokine array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for the treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization, as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cell recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and immunotherapy-resistant metastatic cancer. SIGNIFICANCE: The immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.
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Fulvestrant , Inmunoterapia , Neoplasias Hepáticas , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Animales , Ratones , Femenino , Humanos , Inmunoterapia/métodos , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Antagonistas del Receptor de Estrógeno/farmacología , Antagonistas del Receptor de Estrógeno/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Masculino , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/inmunología , Ratones Endogámicos C57BLRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed that MICAL2 is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Through in vitro phenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential for in vivo tumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypes in vivo . This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.
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Pediatric high-grade gliomas (pHGG) accounts for approximately 8-12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9-15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined. In the present study, we analyzed the response of patient-derived pediatric high-grade glioma cells to a novel IGF-1R inhibitor, the IGF-Trap. Using immunohistochemistry, we found that IGF-1R was localized to both the nucleus and cell membrane in different pHGG patient-derived xenograft (PDX) lines under basal conditions. In response to ligand binding, nuclear levels of the receptor increased, and this was associated with the transcriptional upregulation of both the receptor and cyclin D1, suggesting that IGF-1R could regulate its own expression and cell cycle progression in these cells. Insulin-like growth factor-1 (IGF-1) increased the proliferation of the pHGG cells DIPG13 and SGJ2, and this could be blocked by the addition of the IGF-Trap. The IGF-Trap reduced the colony formation of these cells in an optimal growth medium and impeded the ability of IGF-1 to rescue DIPG13 cells from starvation-induced apoptosis. Collectively, these results implicate the IGF-1 axis in the regulation of cell cycle progression, cellular proliferation, and cell survival in pHGG, and identify the IGF-axis as a target and the IGF-Trap as a potential inhibitor of this axis in pHGG.
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IGF-I receptor (IGF-IR) signaling and functions are mediated through the activities of a complex molecular network of positive (e.g., type I IGF) and negative (e.g., the type II IGF receptor, IGF-IIR) effectors. Under normal physiological conditions, the balance between the expression and activities of these molecules is tightly controlled. Changes in this delicate balance (e.g., overexpression of one effector) may trigger a cascade of molecular events that can ultimately lead to malignancy. In recent years, evidence has been mounting that the IGF axis may be involved in human cancer progression and can be targeted for therapeutic intervention. Here we review old and more recent evidence on the role the IGF system in malignancy and highlight experimental and clinical studies that provide novel insights into the complex mechanisms that contribute to its oncogenic potential. Controversies arising from conflicting evidence on the relevance of IGF-IR and its ligands to human cancer are discussed. Our review highlights the importance of viewing the IGF axis as a complex multifactorial system and shows that changes in the expression levels of any one component of the axis, in a given malignancy, should be interpreted with caution and viewed in a wider context that takes into account the expression levels, state of activation, accessibility, and functionality of other interacting components. Because IGF targeting for anticancer therapy is rapidly becoming a clinical reality, an understanding of this complexity is timely because it is likely to have an impact on the design, mode of action, and clinical outcomes of newly developed drugs.
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Metástasis de la Neoplasia , Neoplasias/patología , Somatomedinas/fisiología , Animales , Ciclo Celular , Transformación Celular Neoplásica , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Humanos , Modelos Biológicos , Procesamiento Proteico-Postraduccional , Tolerancia a Radiación , Receptor IGF Tipo 1/fisiología , Transducción de SeñalRESUMEN
Triple negative breast cancer (TNBC) is associated with unfavorable prognosis and high relapse rates following chemotherapy. There is an urgent need to develop effective targeted therapy for this BC subtype. The type I insulin-like growth factor receptor (IGF-IR) was identified as a potential target for BC management. We previously reported on the production of the IGF-Trap, a soluble IGF-1R fusion protein that reduces the bioavailability of circulating IGF-1 and IGF-2 to the cognate receptor, impeding signaling. In nude mice xenotransplanted with the human TNBC MDA-MB-231 cells, we found variable responses to this inhibitor. We used this model to investigate potential resistance mechanisms to IGF-targeted therapy. We show here that prolonged exposure of MDA-MB-231 cells to the IGF-Trap in vitro selected a resistant subpopulation that proliferated unhindered in the presence of the IGF-Trap. We identified in these cells increased fibroblast growth factor receptor 1 (FGFR1) activation levels that sensitized them to the FGFR1-specific tyrosine kinase inhibitor PD166866. Treatment with this inhibitor caused cell cycle arrest in both the parental and resistant cells, markedly increasing cell death in the latter. When combined with the IGF-Trap, an increase in cell cycle arrest was observed in the resistant cells. Moreover, FGFR1 silencing increased the sensitivity of these cells to IGF-Trap treatment in vivo. Our data identify increased FGFR1 signaling as a resistance mechanism to targeted inhibition of the IGF-IR and suggest that dual IGF-1R/FGFR1 blockade may be required to overcome TNBC cell resistance to IGF-axis inhibitors.
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Resistencia a Antineoplásicos , Receptor IGF Tipo 1/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Ligandos , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor IGF Tipo 1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Trasplante Heterólogo , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti-PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.
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Adenocarcinoma/inmunología , Carcinoma Ductal Pancreático/inmunología , Factores Inmunológicos/inmunología , Terapia de Inmunosupresión/métodos , Inmunoterapia/métodos , Animales , Humanos , Ratones , Metástasis de la Neoplasia , Microambiente TumoralRESUMEN
Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), pancreatic cancer, melanoma, lung cancer and breast cancer, although CRC is the most common primary cancer that metastasizes to the liver. Interactions between tumour cells and the tumour microenvironment play an important part in the engraftment, survival and progression of the metastases. Various cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, parenchymal hepatocytes, dendritic cells, resident natural killer cells as well as other immune cells such as monocytes, macrophages and neutrophils are implicated in promoting and sustaining metastases in the liver. Four key phases (microvascular, pre-angiogenic, angiogenic and growth phases) have been identified in the process of liver metastasis. Imaging modalities such as ultrasonography, CT, MRI and PET scans are typically used for the diagnosis of liver metastases. Surgical resection remains the main potentially curative treatment among patients with resectable liver metastases. The role of liver transplantation in the management of liver metastasis remains controversial. Systemic therapies, newer biologic agents (for example, bevacizumab and cetuximab) and immunotherapeutic agents have revolutionized the treatment options for liver metastases. Moving forward, incorporation of genetic tests can provide more accurate information to guide clinical decision-making and predict prognosis among patients with liver metastases.
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Células Endoteliales , Neoplasias Hepáticas , Bevacizumab , Humanos , Neoplasias Hepáticas/diagnóstico , Microambiente Tumoral , UltrasonografíaRESUMEN
Liver metastases respond poorly to current therapy and remain a frequent cause of cancer-related mortality. We reported previously that tumor cells expressing a soluble form of the insulin-like growth factor-I receptor (sIGFIR) lost the ability to metastasize to the liver. Here, we sought to develop a novel therapeutic approach for prevention of hepatic metastasis based on sustained in vivo delivery of the soluble receptor by genetically engineered autologous bone marrow stromal cells. We found that when implanted into mice, these cells secreted high plasma levels of sIGFIR and inhibited experimental hepatic metastases of colon and lung carcinoma cells. In hepatic micrometastases, a reduction in intralesional angiogenesis and increased tumor cell apoptosis were observed. The results show that the soluble receptor acted as a decoy to abort insulin-like growth factor-I receptor (IGF-IR) functions during the early stages of metastasis and identify sustained sIGFIR delivery by cell-based vehicles as a potential approach for prevention of hepatic metastasis.
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Células de la Médula Ósea/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Receptor IGF Tipo 1/fisiología , Células del Estroma/metabolismo , Células del Estroma/trasplante , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Ratones , Radioinmunoensayo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Retroviridae/genéticaRESUMEN
Glioblastoma multiforme is an aggressive malignancy, resistant to standard treatment modalities and associated with poor prognosis. We analyzed the role of the IGF system in intracerebral glioma growth using human and rat glioma cells. The glioma cells C6 and U87MG were transduced with a genetically engineered retrovirus expressing type 1 insulin-like growth factor (IGF-IR) antisense RNA, either before or after intra-cerebral implantation of the cells into Sprague Dawley rats or nude mice, respectively and tumor growth and animal survival were monitored. Rat glioma cells transduced prior to orthotopic, intra-cerebral implantation had a significantly increased apoptotic rate in vivo and a significantly reduced tumor volume as seen 24 days post implantation (p < 0.0015). This resulted in increased survival, as greater than 70% of the rats were still alive 182 days after tumor implantation (p < 0.01), as compared to 80% mortality by day 24 in the control group. Histomorphology and histochemical studies performed on brain tissue that was obtained from rats that survived for 182 days revealed numerous single cells that were widely disseminated throughout the brain. These cells expressed the ß-galactosidase marker protein, but were Ki67negative, suggesting that they acquired a dormant phenotype. Direct targeting of the C6 cells with retroviral particles in vivo was effective and reduced tumor volumes by 22% relative to controls. A significant effect on tumor growth was also seen with human glioma U87MG cells that were virally transduced and implanted intra-cerebrally in nude mice. We observed in these mice a significant reduction in tumor volumes and 70% of the animals were still alive 6 months after tumor implantation, as compared to 100% mortality in the control group by day 63. Our results show that IGF-IR targeting can inhibit the intracerebral growth of glioma cells. They also suggest that IGF-IR expression levels may determine a delicate balance between glioma cell growth, death and the acquisition of a dormant state in the brain.
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Liver metastases remain a major cause of death from gastrointestinal tract cancers and other malignancies, such as breast and lung carcinomas. Understanding the underlying biology is essential for the design of effective therapies. We previously identified the chemokine CCL7 and its receptor CCR3 as critical mediators of invasion and metastasis in lung and colon carcinoma cells. Here we show that the CCL7/CCR3 axis regulates a late stage in invadopodia genesis namely, the targeting of MMP-9 to the invadopodia complex, thereby promoting invadopodia maturation and collagen degradation. We show that this process could be blocked by overexpression of a dominant negative RhoA in highly invasive cells, while a constitutively active RhoA upregulated invadopodia maturation in CCL7-silenced and poorly invasive and metastatic cells and also enhanced their metastatic potential in vivo, collectively, implicating RhoA activation in signaling downstream of CCL7. Blockade of the ERK or PI3K pathways by chemical inhibitors also inhibited invadopodia formation, but affected the initiation stage of invadopodia genesis. Our data implicate CCL7/CCR3 signaling in invadopodia maturation and suggest that chemokine signaling acts in concert with extracellular matrix-initiated signals to promote invasion and liver metastasis.
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Carcinoma Pulmonar de Lewis/enzimología , Movimiento Celular , Quimiocina CCL7/metabolismo , Colágeno/metabolismo , Neoplasias del Colon/enzimología , Neoplasias Hepáticas/enzimología , Metaloproteinasa 9 de la Matriz/metabolismo , Podosomas/enzimología , Animales , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Quimiocina CCL7/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Metaloproteinasa 9 de la Matriz/genética , Ratones , Fosfatidilinositol 3-Quinasa/metabolismo , Podosomas/genética , Podosomas/patología , Transporte de Proteínas , Proteolisis , Receptores CCR3/genética , Receptores CCR3/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap-a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.
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Anticuerpos Monoclonales/farmacología , Receptor IGF Tipo 1/efectos de los fármacos , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Anticuerpos Monoclonales/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Preparaciones Farmacéuticas/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/efectos de los fármacosRESUMEN
Proper neuronal function requires strict maintenance of the brain's extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood-brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.
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Interactions between endothelial selectins and selectin ligands expressed on tumor cells have been implicated in the binding of circulating metastatic cancer cells to the vascular endothelium during extravasation. Moreover, there is mounting evidence that inflammatory environments can accelerate the progression of metastasis by neutrophil mediated mechanisms. In this study, a physiologically relevant in vivo model of early metastasis coupled with intravital microscopy was used to visualize the trafficking of tumor cells within the liver vasculature in real time. Using GFP-labeled Lewis lung carcinoma subline H-59 cells, we show here that disrupting the interactions between endothelial selectins and tumor cell selectin ligands diminished tumor cell recruitment to the liver. Furthermore, systemic inflammation induced by intravenous injection of lipopolysaccharide significantly enhanced the metastatic potential of these lung carcinoma cells by increasing their propensity to adhere to the liver sinusoidal endothelium. Confocal microscopy revealed frequent colocalization of cancer cells with neutrophils and neutrophil depletion in vivo significantly attenuated the lipopolysaccharide-induced increase in H-59 cell adhesion. Although direct selectin-selectin ligand interactions contributed significantly to tumor cell adhesion to sinusoidal endothelial cells, we show here that in addition, interactions between adherent neutrophils within the inflamed sinusoids and circulating tumor cells may further increase tumor cell arrest in the liver.
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Carcinoma Pulmonar de Lewis/metabolismo , Endotelio Vascular/metabolismo , Inflamación/metabolismo , Hígado/irrigación sanguínea , Neutrófilos/fisiología , Oligosacáridos/metabolismo , Selectinas/metabolismo , Animales , Carcinoma Pulmonar de Lewis/secundario , Adhesión Celular , Progresión de la Enfermedad , Ligandos , Lipopolisacáridos/farmacología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Antígeno Sialil Lewis X , Células Tumorales CultivadasRESUMEN
Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.
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Estrógenos/metabolismo , Neoplasias Hepáticas/secundario , Hígado/patología , Linfocitos Infiltrantes de Tumor/inmunología , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral/trasplante , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Estradiol/administración & dosificación , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Estrógenos/inmunología , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/prevención & control , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Ovariectomía , Neoplasias Pancreáticas/patología , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Factores Sexuales , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Neoplasias PancreáticasRESUMEN
Over the past two decades it has become widely appreciated that a relationship exists between the insulin-like growth factors (IGFs) and cancer. Many cancers have been shown to overexpress the IGF-I receptor and produce the ligands (IGF-I or IGF-II) and some combinations of the six IGF-binding proteins. With the recent demonstration by epidemiological studies that an elevated serum IGF-I level is associated with an increased relative risk of developing a number of epithelial cancers, interest has been sparked in this area of research with the possibility of targeting the IGF-I receptor in cancer treatment protocols. This review highlights many of the most relevant studies in this exciting area of research, focusing in particular on lessons learned from animal models of cancer.
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Hormona del Crecimiento/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Neoplasias/metabolismo , Animales , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Ratones , Modelos Animales , Neoplasias/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidoresRESUMEN
The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor kappaB (NF-kappaB)-mediated tumor necrosis factor alpha (TNF-alpha) production in macrophages. We have previously shown that highly metastatic human and mouse carcinoma cells, on their entry into the hepatic microcirculation, trigger a rapid host proinflammatory response by inducing TNF-alpha production in resident Kupffer cells. Using GeneChip microarray analysis, we found that in mouse Lewis lung carcinoma subclones, SLPI expression was inversely correlated with tumor cell ability to induce a proinflammatory response and metastasize to the liver and with type 1 insulin-like growth factor receptor expression levels. To establish a causal relationship between SLPI expression and the metastatic phenotype, we generated, by transfection, multiple clones of the highly metastatic subline (H-59) that overexpress SLPI. We show here that the ability of these cells to elicit a host proinflammatory response in the liver was markedly decreased, as evidenced by reduced TNF-alpha production and vascular E-selectin expression, relative to controls. Moreover, these cells formed significantly fewer hepatic metastases (up to 80% reduction) as compared with mock-transfected controls. Our findings show that SLPI can decrease the liver-metastasizing potential of carcinoma cells and that this protective effect correlates with a decrease in the production of hepatic TNF-alpha and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis.