RESUMO
The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.
Assuntos
Antineoplásicos/farmacologia , Catepsinas/metabolismo , Macrófagos/patologia , Neoplasias Mamárias Animais/tratamento farmacológico , Paclitaxel/farmacologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Feminino , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Invasividade Neoplásica , Paclitaxel/uso terapêuticoRESUMO
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(µ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(µ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer.
Assuntos
Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Ouro/química , Neoplasias Renais/patologia , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/prevenção & controle , Inibidores de Proteases/farmacologia , Compostos de Rutênio/química , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/enzimologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/enzimologiaRESUMO
Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
Assuntos
Neoplasias Encefálicas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Animais , Neoplasias Encefálicas/secundário , Genes fms , Ativação de Macrófagos , Melanoma , Camundongos , Receptores de Fator Estimulador de Colônias/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Fator de Transcrição STAT5/genética , Neoplasias Cutâneas , Microambiente Tumoral , Melanoma Maligno CutâneoRESUMO
Effective pharmacological treatments for patients with advanced clear cell renal carcinoma (ccRCC) are limited. Bimetallic titanium-gold containing compounds exhibit significant cytotoxicity against ccRCC in vitro and in vivo and inhibit invasion and angiogenisis in vitro and markers driving these phenomena. However, in vivo preclinical evaluations of such compounds have not examined their pharmacokinetics, pathology, and hematology. Here we use NOD.CB17-Prkdc SCID/J mice bearing xenograft ccRCC Caki-1 tumors to evaluate the in vivo efficacies of two titanium-gold compounds Titanocref and Titanofin (based on auranofin analogue scaffolds) accompanied by pharmacokinetic and pathology studies. A therapeutic trial was performed over 21 days at 5 mg/kg/72h of Titanocref and 10 mg/kg/72h of Titanofin tracking changes in tumor size. We observed a significant reduction of 51% and 60%, respectively (p < 0.01) in tumor size in the Titanocref- and Titanofin-treated mice compared to the starting size, while the vehicle-treated mice exhibited a tumor size increase of 138% (p < 0.01). Importantly, no signs of pathological complication as a result of treatment were found. In addition, Titanocref and Titanofin treatment reduced angiogenesis by 38% and 54%, respectively. Microarray and qRT-PCR analysis of ccRCC Caki-1 cells treated with Titanocref revealed that the compound alters apoptosis, JNK MAP kinase, and ROS pathways within 3 h of treatment. We further show activation of apoptosis by Titanocref and Titanofin in vivo by caspase 3 assay. Titanocref is active against additional kidney cancer cells. Titanocref and Titanofin are therefore promising candidates for further evaluation toward clinical application in the treatment of ccRCC.
RESUMO
Water-soluble compounds of the type [AuCl(PR3)] with alkyl-bis-(m-sulfonated-phenyl)-(mC6H4SO3Na)2 and dialkyl-(m-sulfonated-phenyl)-(mC6H4SO3Na) (R = nBu, Cp) phosphanes have been prepared. Dialkyl-phosphane compounds generate water-soluble nanoparticles of 10-15 nm radius when dissolved in water. These air-stable complexes have been evaluated as catalysts in the synthesis of propargylamines via a three-component coupling reaction of aldehydes, amines and alkynes in water. The antimicrobial activity of the new complexes against Gram-positive and Gram-negative bacteria and yeast has been evaluated. The new compounds display moderate to high antibacterial activity. The more lipophilic compounds are also potent against fungi. Their cytotoxic properties have been analyzed in vitro utilizing human Jurkat T-cell acute lymphoblastic leukemia cells. Compounds with dialkyl-(m-sulfonated-phenyl)-(mC6H4SO3Na) phosphanes displayed moderate to high cytotoxicity on this cell line. Death cell mechanism occurs mainly by early apoptosis. The catalytic/biological activity of the previously described compound with commercial m-trisulfonated-triphenylphosphine [AuCl(TPPTS)] (6) has been also evaluated to compare the effects of the higher basicity and lipophilicity of the alkyl- and di-alkyl-(m-sulfonated-phenyl) phosphanes on these new compounds.
RESUMO
BACKGROUND: There are few effective treatments for patients with advanced clear cell renal cell carcinoma (CCRCC). Recent findings indicate that ruthenium-gold containing compounds exhibit significant antitumor efficacy against CCRCC in vitro affecting cell viability as well as angiogenesis and markers driving those 2 phenomena. However, no in vivo preclinical evaluation of this class of compounds has been reported. METHODS: Following the dose-finding pharmacokinetic determination, NOD.CB17-Prkdc SCID/J mice bearing xenograft CCRCC Caki-1 tumors were treated in an intervention trial for 21 days at 10 mg/kg/72h of RANCE-1. At the end of the trial, tumor samples were analyzed for histopathological and changes in protein expression levels were assessed. RESULTS: After 21 days of treatment there was no significant change in tumor size in the RANCE-1-treated mice as compared to the starting size (+3.87%) (P = 0.082) while the vehicle treated mice exhibited a significant tumor size increase (+138%) (P < 0.01). There were no signs of pathological complications as a result of treatment. Significant reduction in the expression of VEGF, PDGF, FGF, EGFR, and HGRF, all key to the proliferation of tumor cells and stromal cells serving protumorigenic purposes was observed. CONCLUSIONS: The tumor growth inhibition displayed and favorable pathology profile of RANCE-1 makes it a promising candidate for further evaluation toward clinical use for the treatment of advanced CCRCC.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Ouro/química , Neoplasias Renais/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Rutênio/química , Proteínas Angiogênicas/metabolismo , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene-gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(η-C5H5)2TiMe(µ-mba)Au(PEt3)] (4) Titanofin. The compound is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(η-C5H5)2TiMe(µ-mba)Au(PPh3)] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(η-C5H5)2TiMe(µ-mba)Au(PR3)] (PR3â¯=â¯PPh32 Titanocref and PEt34 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR3)] (PR3â¯=â¯PPh31 cref; PEt33 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers associated with these processes such as prometastatic IL(s), MMP(s), TNF-α, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overexpressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1α whose overexpression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Compostos Organometálicos/farmacologia , Fosfinas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Renais/patologia , Conformação Molecular , Neovascularização Patológica/patologia , Compostos Organometálicos/química , Fosfinas/química , Relação Estrutura-AtividadeRESUMO
We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest for the synthesis of compounds with potential catalytic and medicinal applications. The general synthetic strategy has been applied in the preparation of novel cationic heterobimetallic ruthenium(ii)-gold(i) complexes that are highly cytotoxic to renal cancer Caki-1 and colon cancer HCT 116 cell lines while showing a synergistic effect and being more selective than their monometallic counterparts.
Assuntos
Ouro/química , Compostos Heterocíclicos/síntese química , Metano/análogos & derivados , Rutênio/química , Cátions , Ligantes , Metano/químicaRESUMO
A series of new organometallic carbosilane dendrimers (first and second generation) and the corresponding non-dendritic mononuclear based on ruthenium arene fragments are described. The metallodendrimers were prepared by reactions of the precursor [Ru(η(6)-p-cymene)Cl2]2 with carbosilane dendrimers functionalized with N-donor monodentate ligands such as NH2- and pyridine, or with N,O-, N,N-chelating imine ligands. While the dendrimer precursors are insoluble in DMSO or water, novel metallodendrimers are soluble in DMSO and some of them are even highly soluble in water. The molecular structure of the "Ru-NH2" mononuclear compound (zero generation) was determined by single-crystal X-ray crystallography. The cytotoxicity activity of these dendritic structures was evaluated in several human cancer cell lines and compared with that of the corresponding mononuclear ruthenium complexes. Most compounds display significant cytotoxic activities in the low micromolar range with the first generation ruthenium dendrimers being the most active compounds. The cell death type for selected compounds has been studied as well as their reactivity towards relevant biomolecules such as DNA, Human Serum Albumin (HSA) and Cathepsin-B. All the data point to a mode of action different from that of cisplatin for most complexes. First generation ruthenium dendrimers inhibit Cathepsin-B, which may suggest potential antimetastatic properties of these compounds.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Dendrímeros/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Rutênio/química , Silanos/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Catepsina B/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , DNA/metabolismo , Humanos , Ligantes , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Albumina Sérica/metabolismoRESUMO
We report on the synthesis, characterization, and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = -OC(O)-p-C6H4-S-) bound to gold(I)-N-heterocyclic carbene fragments through the thiolate group: [(η5-C5H5)2TiMe(µ-mba)Au(NHC)]. The cytotoxicities of the heterometallic compounds along with those of novel monometallic gold-N-heterocyclic carbene precursors [(NHC)Au(mbaH)] have been evaluated against renal, prostate, colon, and breast cancer cell lines. The highest activity and selectivity and a synergistic effect of the resulting heterometallic species was found for the prostate and colon cancer cell lines. The colocalization of both titanium and gold metals (1:1 ratio) in PC3 prostate cancer cells was demonstrated for the selected compound 5a, indicating the robustness of the heterometallic compound in vitro. We describe here preliminary mechanistic data involving studies on the interaction of selected mono- and bimetallic compounds with plasmid (pBR322) used as a model nucleic acid and the inhibition of thioredoxin reductase in PC3 prostate cancer cells. The heterometallic compounds, which are highly apoptotic, exhibit strong antimigratory effects on the prostate cancer cell line PC3.
RESUMO
The synthesis and characterization of new enantiopure cyclopentadienyl titanium oximato compounds (S,R)-[(η(5)-C5H5)Ti{к(2)NO,(R)NH·HCl}Cl2] (R=Ph (phenyl) 1a·HCl, Bn (benzyl) 1b·HCl, 2-pic (2-picolyl) 1c·HCl), (S,R)-[(η(5)-C5H5)TiCl2{к(2)NO,(Ph)NH}] (1a) and (S,R)-[(η(5)-C5H5)2TiCl{к(2)NO,(R)NH}] (R=Ph 2a, Bn 2b, 2-pic 2c), along with studies on their behavior in D2O at different pD values are reported. The structure of previously described ammonium-oxime (2S,5R)-{NOH,(Bn)NH·HCl} (b·HCl) and novel titanium derivative 1a have been determined by single crystal X-ray crystallography. The effect of the compounds on cytotoxicity, cell adhesion and migration of the androgen-independent prostate cancer PC-3 cells has been assessed. Compounds 2b and 2c are more cytotoxic than additive doses of titanocene dichloride and free oxime proligand, probing the synergistic effect of these novel compounds. The cytotoxicity of 2b and 2c has been further evaluated against human renal Caki-1, colon DLD-1 and triple negative breast MDA-MB-231 cancer cell lines. The activity found for 2c on PC-3 and Caki-1 is higher than that of highly active Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride), while showing selectivity against renal cancer when compared to a non-tumorigenic human renal (HEK-293T) cell line. Compounds 2b and especially 2c are apoptotic in Caki-1 cancer cell lines. Cell adhesion and wound-healing assays confirmed that derivatives 1c·HCl, 2b and 2c affect the adhesion and migration patterns of the PC-3 cell line. Interactions of the novel compounds with plasmid (pBR322) DNA have also been studied, showing that the oximato Ti(IV) derivatives have a weak or no interaction with DNA at physiological pH.
Assuntos
Antineoplásicos/química , Titânio/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectroscopia de Infravermelho com Transformada de Fourier , EstereoisomerismoRESUMO
Following recent work on heterometallic titanocene-gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S-C6H4-COO-) bound to gold(I)-phosphane fragments through a thiolate group ([(η-C5H5)2TiMe(µ-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 ([(η-C5H5)2TiMe(µ-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1:1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg/kg/every other day) with heterometallic compound 5 as compared with the previously described [(η-C5H5)2Ti{OC(O)-4-C6H4-P(Ph2)AuCI}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.
RESUMO
Early-late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = -CH2- 6, -4-C6H4- 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics.
RESUMO
A series of organometallic ruthenium(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70-100 mg/mL). Most compounds (especially highly water-soluble 2) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of 2 in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Complexos de Coordenação/síntese química , Compostos Organometálicos/síntese química , Compostos Organometálicos/uso terapêutico , Rutênio/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/uso terapêutico , Feminino , Células HEK293 , Humanos , Técnicas In Vitro , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforanos/síntese química , Fosforanos/uso terapêutico , Solubilidade , ÁguaRESUMO
Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.