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1.
Nat Cell Biol ; 21(4): 511-521, 2019 04.
Article in English | MEDLINE | ID: mdl-30886344

ABSTRACT

Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1F/F;Trp53F/F transgenic mouse model for breast cancer stimulates intratumoural type I interferon (IFN) signalling, which enhances the anticancer efficacy of platinum-based chemotherapeutics. Notably, anti-CSF-1R treatment also increased intratumoural expression of type I IFN-stimulated genes in patients with cancer, confirming that CSF-1R blockade is a powerful strategy to trigger an intratumoural type I IFN response. By inducing an inflamed, type I IFN-enriched tumour microenvironment and by further targeting immunosuppressive neutrophils during cisplatin therapy, antitumour immunity was activated in this poorly immunogenic breast cancer mouse model. These data illustrate the importance of breaching multiple layers of immunosuppression during cytotoxic therapy to successfully engage antitumour immunity in breast cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon Type I/physiology , Mammary Neoplasms, Experimental/drug therapy , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Cell Line, Tumor , Cisplatin/therapeutic use , Female , Humans , Immunity, Innate/drug effects , Macrophages/drug effects , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Knockout , Mice, Transgenic
2.
J Clin Neurosci ; 62: 207-211, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30678836

ABSTRACT

Advances in therapies for breast cancer with cerebral metastases has been slow, despite this being a common diagnosis, due to limited drug delivery by the blood brain barrier. Improvements in drug delivery for brain metastasis to target the metastases and bypass the blood brain barrier are necessary. In our study, we delivered an inhibitor of chemokine receptor 4 by convection enhanced delivery in a hyperosmotic solution to prevent brain metastasis in a mouse model of metastatic breast cancer. We found the inhibitor limited metastatic disease and more interestingly, the hyperosmotic solution targeted tumor tissue allowing for a higher accumulation of the therapy into tumor tissue. This finding has the potential to improve delivery of chemotherapeutic agents to brain metastases.


Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/secondary , Drug Delivery Systems/methods , Mammary Neoplasms, Experimental/secondary , Receptors, CXCR4/antagonists & inhibitors , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Injections, Intraventricular , Mice , Mice, Nude , Osmolar Concentration , Xenograft Model Antitumor Assays
3.
Biochem Cell Biol ; 96(6): 825-831, 2018 12.
Article in English | MEDLINE | ID: mdl-29894647

ABSTRACT

Despite the great progress in recent years, many aspects of the pathogenesis and progression of breast cancer remain unclear. A better understanding on the molecular mechanisms underlying metastasis and recurrence is crucial to improve the treatment of this lethal disease. MCF-7 cells were xenografted into mice until visible tumors developed, and the cells from tumor tissue and adjacent normal tissue were cultured with 3 passages as mass tumor (MT) cells and invasive tumor (IT) cells, respectively. Microarray analysis was performed to detect several viable microRNAs in these 2 types of cells. Further, miR-30 knockdown was used to investigate its role in tumor aggression. Relative levels of miR-30 were significantly higher in IT cells than MT cells. Knockdown of miR-30 in both MT and IT cells lowered cell proliferation and cell invasion abilities, and thus increased the survival time of mice xenografted with tumor cells. This study suggested that the knockdown of miR-30 decreased proliferation and invasion of carcinoma cells, giving rise to the potential of miR-30 as a tumor target or marker candidate for breast cancer therapy.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , MicroRNAs/metabolism , Animals , Cell Proliferation , Female , Humans , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness/genetics , Neoplasm Metastasis/genetics
4.
Bone ; 113: 77-88, 2018 08.
Article in English | MEDLINE | ID: mdl-29753718

ABSTRACT

The tumor-cell microenvironment is recognized as a dynamic place where critical cell interactions occur and play an important role in altering tumorigenesis. While many studies have investigated the effects of cellular cross-talk within distinct tumor microenvironments, these interactions have yet to be fully examined in bone. It is well-established that many common cancers metastasize to bone, resulting in the development of tumor-induced bone disease (TIBD), a multi-facetted illness that is driven by complex cell interactions within the bone marrow. Our group has previously published that myeloid progenitor cells expand in the presence of tumors in bone, aligning with the notion that myeloid cells can act as tumor promotors. Several groups, including ours, have established that transforming growth factor ß (TGF-ß), an abundant growth factor in bone, can regulate both TIBD and myeloid expansion. TGF-ß inhibitors have been shown to increase bone volume, decrease bone destruction, and reduce but not eliminate tumor. Therefore, we hypothesize that inhibiting TGF-ß will reduce myeloid expansion leading to a reduction of tumor burden in bone and osteoclast-mediated bone loss, causing to an overall reduction in TIBD. To address this hypothesis, two different mouse models of breast cancer bone colonization were pre-treated with the TGF-ß neutralizing antibody, 1D11, prior to tumor inoculation (athymic: MDA-MB-231, BALB/c: 4T1) and continuously treated until sacrifice. Additionally, a genetically modified mouse model with a myeloid specific deletion of transforming growth factor beta receptor II (TGF-ßRII) (TGF-ßRIIMyeKO) was utilized in our studies. Systemic inhibition of TGF-ß lead to fewer osteolytic lesions, and reduced tumor burden in bone as expected from previous studies. Additionally, early TGF-ß inhibition affected expansion of distinct myeloid populations and shifted the cytokine profile of pro-tumorigenic factors in bone, 4T1 tumor cells, and bone-marrow derived macrophages. Similar observations were seen in tumor-bearing TGF-ßRIIMyeKO mice, where these mice contained fewer bone lesions and significantly less tumor burden in bone, suggesting that TGF-ß inhibition regulates myeloid expansion leading to a significant reduction in TIBD.


Subject(s)
Bone Neoplasms/secondary , Mammary Neoplasms, Experimental/secondary , Myeloid Progenitor Cells/pathology , Transforming Growth Factor beta/antagonists & inhibitors , Tumor Microenvironment/physiology , Animals , Female , Humans , Mice , Mice, Knockout
5.
Am J Med Sci ; 354(1): 54-63, 2017 07.
Article in English | MEDLINE | ID: mdl-28755734

ABSTRACT

BACKGROUND: Cancer stem cells are a subpopulation of tumor cells that are capable of self-renewal, capable of tumor recurrence and metastasis, and in addition are resistant to current cancer therapies. Epigallocatechin-3-gallate is a type of catechin found in green tea that is known for its powerful chemoprotective ability. Hence, this study aimed to investigate the effect of epigallocatechin-3-gallate on 7, 12 dimethylbenzanthracene-induced tumor metastasis, angiogenesis and cancer stem cells. MATERIALS AND METHODS: For this purpose, 3 groups of virgin femal rats with 7,12 dimethylbenzanthracene-induced mammary cancer were treated using epigallocatechin-3-gallate, paclitaxel or their combination. RESULTS: It was found that epigallocatechin-3-gallate exhibited significant chemopreventive effects and anti-cancer stem cell activity through several pathways, including a significant decrease in the size and number of tumors per rat, significant amelioration of the oxidative stress markers' alterations and significant inhibition of CD44, VEGF, Ki-67 and MMP-2 expression associated with a significantly increased expression of caspase-3. Histopathologically, therapy with epigallocatechin-3-gallate resulted in marked necrosis of the neoplastic cells and the tumor masses were mostly replaced by proliferated fibrous tissue so that histological confirmation of a previous tumor was not possible at that site. However, in the combination therapy the neoplastic cells showed marked vacuolation, haphazard arrangement and extensive nuclear pyknosis accompanied with many apoptotic bodies. Therapy with the sole paclitaxel caused variable degrees of necrosis among the neoplastic cells. Additionally, the combination of epigallocatechin-3-gallate and paclitaxel significantly enhanced the later anticancer efficacy. CONCLUSIONS: Epigallocatechin-3-gallatecould be offered as an unprecedented curative strategy to eradicate cancer.


Subject(s)
Anticarcinogenic Agents/pharmacology , Catechin/analogs & derivatives , Mammary Neoplasms, Experimental/drug therapy , Neoplastic Stem Cells/drug effects , 9,10-Dimethyl-1,2-benzanthracene/pharmacology , Animals , Carcinogens/pharmacology , Catechin/pharmacology , Female , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/secondary , Rats , Rats, Sprague-Dawley
6.
Acta Pharmacol Sin ; 38(6): 924-930, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28504249

ABSTRACT

Cancer metastasis is the primary cause of high mortality in breast cancer patients. In this study, we loaded an anti-cancer drug, cabazitaxel (CTX), into polymeric micelles (CTX-loaded polymeric micelles, PCMs), and explored their therapeutic efficacy in breast cancer metastasis. The characteristics of PCMs were investigated, and their anti-metastatic efficacy was assessed using in vitro and in vivo evaluations. PCMs had an average diameter of 50.13±11.96 nm with a CTX encapsulation efficiency of 97.02%±0.97%. PCMs could be effectively internalized into metastatic 4T1 breast cancer cells in vitro. CTX (10 ng/mL) or an equivalent concentration in PCMs did not significantly affected the viability of 4T1 cells, but dramatically decreased the cell migration activities. In an orthotopic metastatic breast cancer model, intravenously administered PCMs could be efficiently delivered to the tumor sites, resulting in a 71.6% inhibition of tumor growth and a 93.5% reduction of lung metastases. Taken together, our results verify the anti-metastatic efficacy of PCMs, thus providing an encouraging strategy for treating breast cancer metastasis.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Lactates/chemistry , Polyethylene Glycols/chemistry , Taxoids/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Breast Neoplasms/pathology , Breast Neoplasms/secondary , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Lactates/administration & dosage , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Inbred BALB C , Mice, Nude , Micelles , Particle Size , Polyethylene Glycols/administration & dosage , Structure-Activity Relationship , Surface Properties , Taxoids/administration & dosage , Taxoids/chemistry
7.
Sci Rep ; 6: 36173, 2016 11 04.
Article in English | MEDLINE | ID: mdl-27812027

ABSTRACT

This study aimed at evaluating the reliability and precision of Diffuse Luminescent Imaging Tomography (DLIT) for monitoring primary tumor and metastatic spreading in breast cancer mice, and to develop a biomathematical model to describe the collected data. Using orthotopic mammary fat pad model of breast cancer (MDAMB231-Luc) in mice, we monitored tumor and metastatic spreading by three-dimensional (3D) bioluminescence and cross-validated it with standard bioluminescence imaging, caliper measurement and necropsy examination. DLIT imaging proved to be reproducible and reliable throughout time. It was possible to discriminate secondary lesions from the main breast cancer, without removing the primary tumor. Preferential metastatic sites were lungs, peritoneum and lymph nodes. Necropsy examinations confirmed DLIT measurements. Marked differences in growth profiles were observed, with an overestimation of the exponential phase when using a caliper as compared with bioluminescence. Our mathematical model taking into account the balance between living and necrotic cells proved to be able to reproduce the experimental data obtained with a caliper or DLIT imaging, because it could discriminate proliferative living cells from a more composite mass consisting of tumor cells, necrotic cell, or inflammatory tissues. DLIT imaging combined with mathematical modeling could be a powerful and informative tool in experimental oncology.


Subject(s)
Breast Neoplasms/diagnostic imaging , Breast Neoplasms/secondary , Mammary Neoplasms, Experimental/secondary , Animals , Cell Line, Tumor , Female , Heterografts , Humans , Imaging, Three-Dimensional , Luminescent Measurements , Mammary Neoplasms, Experimental/diagnostic imaging , Mice , Models, Biological , Reproducibility of Results , Tomography, Optical/methods
8.
Adv Exp Med Biol ; 904: 41-58, 2016.
Article in English | MEDLINE | ID: mdl-26900062

ABSTRACT

In recent years, our serial investigations focused on the role of cancer cells-derived endogenous formaldehyde in bone cancer pain. We found that cancer cells produced formaldehyde through demethylation process by serine hydroxymethyltransferase (SHMT1 and SHMT2) and lysine-specific histone demethylase 1 (LSD1). When the cancer cells metastasized into bone marrow, the elevated endogenous formaldehyde induced bone cancer pain through activation on the transient receptor potential vanilloid subfamily member 1 (TRPV1) in the peripheral nerve fibers. More interestingly, TRPV1 expressions in the peripheral fibers were upregulated by the local insulin-like growth factor I (IGF-I) produced by the activated osteoblasts. In conclusion, tumor tissue-derived endogenous formaldehyde induced bone cancer pain via TRPV1 activation.


Subject(s)
Bone Neoplasms/metabolism , Cancer Pain/physiopathology , Formaldehyde/metabolism , Neoplasm Proteins/physiology , Peripheral Nerves/metabolism , TRPV Cation Channels/physiology , Animals , Bone Neoplasms/pathology , Bone Neoplasms/physiopathology , Cancer Pain/drug therapy , Capsaicin/pharmacology , Cells, Cultured , Glycine Hydroxymethyltransferase/metabolism , Histone Demethylases/metabolism , Humans , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/pharmacology , Mammary Neoplasms, Experimental/physiopathology , Mammary Neoplasms, Experimental/secondary , Osteoblasts/metabolism , Peripheral Nerves/physiopathology , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/therapeutic use , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/biosynthesis , TRPV Cation Channels/genetics
9.
Proc Natl Acad Sci U S A ; 113(8): 2223-8, 2016 Feb 23.
Article in English | MEDLINE | ID: mdl-26858439

ABSTRACT

Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed "tumor self-seeding." Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as "tumor self-targeting." For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.


Subject(s)
Neoplasms, Experimental/therapy , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Apoptosis , Carcinoma, Lewis Lung/pathology , Carcinoma, Lewis Lung/secondary , Carcinoma, Lewis Lung/therapy , Cell Engineering , Cell Line, Tumor , Cell- and Tissue-Based Therapy , Drug Delivery Systems , Endothelium, Vascular/pathology , Female , Humans , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mammary Neoplasms, Experimental/therapy , Melanoma, Experimental/pathology , Melanoma, Experimental/secondary , Melanoma, Experimental/therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms, Experimental/pathology , Neoplasms, Experimental/secondary , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , Transduction, Genetic , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/therapeutic use , Xenograft Model Antitumor Assays
10.
PLoS One ; 10(7): e0134458, 2015.
Article in English | MEDLINE | ID: mdl-26222311

ABSTRACT

The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness.


Subject(s)
Galectin 3/metabolism , Mammary Neoplasms, Experimental/metabolism , Animals , Cell Line, Tumor , Disease Progression , Dogs , Female , Galectin 3/genetics , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/metabolism , Hypoxia/metabolism , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/secondary , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/secondary , Mice, Nude , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Transplantation, Heterologous , Tumor Microenvironment , Up-Regulation
11.
PLoS One ; 9(9): e105079, 2014.
Article in English | MEDLINE | ID: mdl-25188396

ABSTRACT

Circulating tumor cells (CTCs) have been detected in the bloodstream of both early-stage and advanced cancer patients. However, very little is know about the dynamics of CTCs during cancer progression and the clinical relevance of longitudinal CTC enumeration. To address this, we developed a simple bioluminescence imaging assay to detect CTCs in mouse models of metastasis. In a 4T1 orthotopic metastatic mammary carcinoma mouse model, we demonstrated that this quantitative method offers sensitivity down to 2 CTCs in 0.1-1mL blood samples and high specificity for CTCs originating from the primary tumor, independently of their epithelial status. In this model, we simultaneously monitored blood CTC dynamics, primary tumor growth, and lung metastasis progression over the course of 24 days. Early in tumor development, we observed low numbers of CTCs in blood samples (10-15 cells/100 µL) and demonstrated that CTC dynamics correlate with viable primary tumor growth. To our knowledge, these data represent the first reported use of bioluminescence imaging to detect CTCs and quantify their dynamics in any cancer mouse model. This new assay is opening the door to the study of CTC dynamics in a variety of animal models. These studies may inform clinical decision on the appropriate timing of blood sampling and value of longitudinal CTC enumeration in cancer patients.


Subject(s)
Luminescent Measurements/methods , Mammary Neoplasms, Experimental/blood , Neoplastic Cells, Circulating/pathology , Animals , Cell Line, Tumor , Disease Progression , Female , Hemolysis , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Nude , Neoplasm Invasiveness/pathology
13.
Proc Natl Acad Sci U S A ; 111(32): 11774-9, 2014 Aug 12.
Article in English | MEDLINE | ID: mdl-25071169

ABSTRACT

Impressive responses have been observed in patients treated with checkpoint inhibitory anti-programmed cell death-1 (PD-1) or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti-PD-1 and anti-CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.


Subject(s)
Immunotherapy/methods , Myeloid Cells/immunology , Neoplasm Metastasis/immunology , Neoplasm Metastasis/therapy , Animals , Antibodies, Monoclonal/administration & dosage , Azacitidine/administration & dosage , Benzamides/administration & dosage , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Cell Line, Tumor , Colorectal Neoplasms/immunology , Colorectal Neoplasms/secondary , Colorectal Neoplasms/therapy , Combined Modality Therapy , Epigenesis, Genetic/drug effects , Female , Histone Deacetylase Inhibitors/administration & dosage , Humans , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/secondary , Mammary Neoplasms, Experimental/therapy , Mice , Mice, Inbred BALB C , Myeloid Cells/drug effects , Neoplasm Metastasis/genetics , Phosphoinositide-3 Kinase Inhibitors , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Pyridines/administration & dosage
14.
Sci Transl Med ; 6(242): 242ra84, 2014 Jun 25.
Article in English | MEDLINE | ID: mdl-24964992

ABSTRACT

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Cyclooxygenase 2 Inhibitors/therapeutic use , Liver Neoplasms/prevention & control , Liver Neoplasms/secondary , Mammary Neoplasms, Experimental/prevention & control , Mammary Neoplasms, Experimental/secondary , Xenograft Model Antitumor Assays , Angiogenesis Inhibitors/pharmacology , Animals , Axitinib , Carcinogenesis/pathology , Cell Line, Tumor , Clone Cells , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dinoprostone/metabolism , Female , Humans , Imidazoles/pharmacology , Indazoles/pharmacology , Liver Neoplasms/blood supply , Liver Neoplasms/drug therapy , Mammary Neoplasms, Experimental/blood supply , Mammary Neoplasms, Experimental/drug therapy , Mice , Neoadjuvant Therapy , Signal Transduction/drug effects , Survival Analysis , Vascular Endothelial Growth Factor A/metabolism
15.
Mol Cell Biol ; 34(17): 3229-43, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24934442

ABSTRACT

While the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control.


Subject(s)
E2F Transcription Factors/physiology , Mammary Neoplasms, Experimental/etiology , Animals , Antigens, Polyomavirus Transforming , E2F Transcription Factors/deficiency , E2F Transcription Factors/genetics , E2F1 Transcription Factor/deficiency , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/physiology , E2F2 Transcription Factor/deficiency , E2F2 Transcription Factor/genetics , E2F2 Transcription Factor/physiology , E2F3 Transcription Factor/deficiency , E2F3 Transcription Factor/genetics , E2F3 Transcription Factor/physiology , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/secondary , Mammary Tumor Virus, Mouse , Mice , Mice, Knockout , Neoplastic Cells, Circulating/pathology , Neovascularization, Pathologic/genetics , Retroviridae Infections/etiology , Retroviridae Infections/pathology , Signal Transduction , Tumor Microenvironment , Tumor Virus Infections/etiology , Tumor Virus Infections/pathology
16.
Mol Ther ; 21(11): 1996-2007, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24081029

ABSTRACT

The ERBB receptors are a family of heterodimerization partners capable of driving transformation and metastasis. While the therapeutic targeting of single receptors has proven efficacious, optimal targeting of this receptor family should target all oncogenic members simultaneously. The juxtamembrane domains of ERBB1, ERBB2, and ERBB3 are highly conserved and control various aspects of ERBB-dependent biology. In an effort to block those functions, we have targeted this domain with decoy peptides synthesized in tandem with a cell-penetrating peptide, termed EJ1. Treatment with EJ1 induces cell death, promotes the formation of inactive ERBB multimers, and results in simultaneous reduction of ERBB1, ERBB2, and ERBB3 activation. Treatment also results in the activation of myosin light chain-dependent cell blebbing while inactivating CaMKII signaling, coincident with the induction of cell death. EJ1 also directly translocates to mitochondria, correlating with a loss of mitochondrial membrane potential and production of reactive oxygen species. Finally, treatment of a mouse model of breast cancer with EJ1 results in the inhibition of tumor growth and metastasis without associated toxicities in normal cells. Overall, these data demonstrate that a portion of the ERBB jxm domain, when used as an intracellular decoy, can inhibit tumor growth and metastasis, representing a novel anticancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Cell-Penetrating Peptides/pharmacology , Lung Neoplasms/drug therapy , Mammary Neoplasms, Experimental/drug therapy , Neoplasm Metastasis/drug therapy , Reactive Oxygen Species/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Cell-Penetrating Peptides/therapeutic use , Disease Progression , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Transgenic , Mitochondria/metabolism , Protein Multimerization/drug effects , Receptor Protein-Tyrosine Kinases/chemistry , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/chemistry , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/chemistry , Receptor, ErbB-3/metabolism , Signal Transduction/drug effects
17.
Anticancer Drugs ; 24(4): 344-54, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23407059

ABSTRACT

Emend, an NK1 antagonist, and dexamethasone are used to treat complications associated with metastatic brain tumours and their treatment. It has been suggested that these agents exert anticancer effects apart from their current use. The effects of the NK1 antagonists, Emend and N-acetyl-L-tryptophan, and dexamethasone on tumour growth were investigated in vitro and in vivo at clinically relevant doses. For animal experiments, a stereotaxic injection model of Walker 256 rat breast carcinoma cells into the striatum of Wistar rats was used. Emend treatment led to a decrease in tumour cell viability in vitro, although this effect was not replicated by N-acetyl-L-tryptophan. Dexamethasone did not decrease tumour cell viability in vitro but decreased tumour volume in vivo, likely to be through a reduction in tumour oedema, as indicated by the increase in tumour cell density. None of the agents investigated altered tumour cell replication or apoptosis in vivo. Inoculated animals showed increased glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 immunoreactivity indicative of astrocytes and microglia in the peritumoral area, whereas treatment with Emend and dexamethasone reduced the labelling for both glial cells. These results do not support the hypothesis that NK1 antagonists or dexamethasone exert a cytotoxic action on tumour cells, although these conclusions may be specific to this model and cell line.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/secondary , Carcinoma/secondary , Dexamethasone/pharmacology , Mammary Neoplasms, Experimental/secondary , Morpholines/pharmacology , Neoplasm Proteins/antagonists & inhibitors , Neurokinin-1 Receptor Antagonists , Tryptophan/analogs & derivatives , Animals , Aprepitant , Astrocytes/pathology , Brain Edema/etiology , Brain Edema/prevention & control , Brain Neoplasms/complications , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Calcium-Binding Proteins/analysis , Carcinoma/drug therapy , Cell Line, Tumor/drug effects , Cell Line, Tumor/transplantation , Corpus Striatum/pathology , Dexamethasone/administration & dosage , Drug Screening Assays, Antitumor , Female , Glial Fibrillary Acidic Protein/analysis , Humans , In Vitro Techniques , Male , Mammary Neoplasms, Experimental/drug therapy , Microfilament Proteins/analysis , Microglia/pathology , Models, Biological , Morpholines/administration & dosage , Morpholines/therapeutic use , Neoplasm Proteins/physiology , Random Allocation , Rats , Rats, Wistar , Receptors, Neurokinin-1/physiology , Tryptophan/administration & dosage , Tryptophan/pharmacology , Tumor Burden/drug effects , Tumor Microenvironment
18.
J Clin Invest ; 122(10): 3718-30, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22945631

ABSTRACT

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.


Subject(s)
Antibodies, Monoclonal/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , CTLA-4 Antigen/antagonists & inhibitors , Immunotherapy , Lymphocytes, Tumor-Infiltrating/drug effects , Mammary Neoplasms, Experimental/therapy , Animals , Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/radiation effects , Cell Line, Tumor/immunology , Cell Line, Tumor/transplantation , Cell Movement , Combined Modality Therapy , Cytotoxicity, Immunologic/drug effects , Cytotoxicity, Immunologic/radiation effects , Drug Screening Assays, Antitumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/radiation effects , H-2 Antigens/immunology , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/radiation effects , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/radiotherapy , Mammary Neoplasms, Experimental/secondary , Mice , Mice, Inbred BALB C , NK Cell Lectin-Like Receptor Subfamily K/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily K/immunology , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Nuclear Matrix-Associated Proteins/biosynthesis , Nuclear Matrix-Associated Proteins/genetics , Nucleocytoplasmic Transport Proteins/biosynthesis , Nucleocytoplasmic Transport Proteins/genetics , Receptors, CXCR/genetics , Receptors, CXCR6 , Tumor Microenvironment/immunology
19.
Int J Dev Biol ; 55(7-9): 671-84, 2011.
Article in English | MEDLINE | ID: mdl-22161824

ABSTRACT

The present review describes molecular and cellular mechanisms of cancer invasion and metastasis as compared to mammary gland development considering communication inside and between ecosystems. At the level of the individual cell, invasion programs are written by an ecosystem of signalling pathways each of which steers several invasion-related cellular activities. At the supracellular level, communication within the epithelial compartment involves cells of the same origin, but with different phenotypes including stem cells. A similar interaction occurs between the various cells of the stromal compartment. Crucial for our understanding of tumor or mammary gland ecosystems are the mutual interactions between cells of the epithelial and cells of the stromal compartment. An update is provided for endothelial cells, cancer-associated fibroblasts and macrophages that are implicated in angiogenesis, desmoplasia and inflammation respectively. At the level of the organism, distant ecosystems, comprising primary tumor site, sites of metastasis, bone marrow and endocrine glands among others, are in continuous contact through circulating cells and soluble ligands. Our review suggests consideration of these ecosystems when designing therapeutic strategies.


Subject(s)
Breast Neoplasms/pathology , Breast/growth & development , Animals , Breast Neoplasms/physiopathology , Breast Neoplasms/secondary , Cell Communication , Endothelial Cells/pathology , Endothelial Cells/physiology , Epithelial Cells/pathology , Epithelial Cells/physiology , Female , Humans , Mammary Glands, Animal/growth & development , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/physiopathology , Mammary Neoplasms, Experimental/secondary , Mice , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/physiopathology , Neoplasm Metastasis/pathology , Neoplasm Metastasis/physiopathology , Neovascularization, Pathologic , Signal Transduction , Stem Cell Niche , Stromal Cells/pathology , Stromal Cells/physiology , Tumor Microenvironment
20.
Int J Hyperthermia ; 27(6): 563-72, 2011.
Article in English | MEDLINE | ID: mdl-21846192

ABSTRACT

PURPOSE: The purpose of this study was to explore the effects of MIH and radiotherapy alone or combined on metastatic breast cancer and the underlying mechanisms. MATERIALS AND METHODS: A murine 4T1 metastatic breast cancer model was established and randomly assigned into four treatment groups: C (control), R (radiotherapy), MIH, and MIH+R. Tumour volume, lung metastasis, the expression of Bax and MMP-9, T cell subsets, serum cytokine levels, and mouse survival were evaluated. RESULTS: Group MIH + R showed significantly reduced tumour volume, lung metastasis, improved survival and increased Bax expression compared to group R or MIH (P<0.05). MMP-9 expression in the primary tumour tissue was significantly increased in group R compared to the other groups (P<0.05), which could be brought down by combined MIH treatment. Group MIH +R showed significantly higher CD4(+) T cell percentage as well as CD4(+)/CD8(+) cell ratio than group R (P<0.05). Group MIH+R showed significantly higher serum levels of TNF-α, IFN-γ and IL-2 than group R (P<0.05). CONCLUSIONS: MIH not only promotes the tumour-cell killing effect of radiotherapy through Bax-mediated cell death, but also improves cellular immunity in mice under radiotherapy and decreases the potential of radiotherapy to enhance MMP-9 expression, which leads to significant improvement in lung metastasis and overall survival of mice under combined treatment of MIH and R. This study is the first to have explored the effect of combined hyperthermia and radiotherapy on tumour metastasis and the underlying mechanisms. It provides insights into the application of MIH as an adjuvant to radiotherapy for metastatic breast cancer.


Subject(s)
Hyperthermia, Induced/methods , Magnetics , Mammary Neoplasms, Experimental/therapy , Animals , Cell Line, Tumor , Combined Modality Therapy , Cytokines/blood , Female , Immunity, Cellular , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/radiotherapy , Mammary Neoplasms, Experimental/secondary , Matrix Metalloproteinase 9/biosynthesis , Mice , Survival Analysis , T-Lymphocyte Subsets/radiation effects , bcl-2-Associated X Protein
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