RESUMEN
Prostate cancers have a strong propensity to metastasize to bone and promote osteoblastic lesions. TMPRSS2:ERG is the most frequent gene rearrangement identified in prostate cancer, but whether it is involved in prostate cancer bone metastases is largely unknown. We exploited an intratibial metastasis model to address this issue and we found that ectopic expression of the TMPRSS2:ERG fusion enhances the ability of prostate cancer cell lines to induce osteoblastic lesions by stimulating bone formation and inhibiting the osteolytic response. In line with these in vivo results, we demonstrate that the TMPRSS2:ERG fusion protein increases the expression of osteoblastic markers, including Collagen Type I Alpha 1 Chain and Alkaline Phosphatase, as well as Endothelin-1, a protein with a documented role in osteoblastic bone lesion formation. Moreover, we determined that the TMPRSS2:ERG fusion protein is bound to the regulatory regions of these genes in prostate cancer cell lines, and we report that the expression levels of these osteoblastic markers are correlated with the expression of the TMPRSS2:ERG fusion in patient metastasis samples. Taken together, our results reveal that the TMPRSS2:ERG gene fusion is involved in osteoblastic lesion formation induced by prostate cancer cells.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Osteoblastos/metabolismo , Neoplasias de la Próstata/genética , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Línea Celular Tumoral , Cadena alfa 1 del Colágeno Tipo I , Endotelina-1/genética , Endotelina-1/metabolismo , Humanos , Masculino , Ratones SCID , Proteínas de Fusión Oncogénica/metabolismo , Osteoblastos/patología , Células PC-3 , Fenotipo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Trasplante Heterólogo , Carga Tumoral/genéticaRESUMEN
The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia. This review focuses on the mutations associated with opsismodysplasia and explores the role of INPPL1/ SHIP2 in skeletal development.
Asunto(s)
Desarrollo Óseo/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Fosfatos de Fosfatidilinositol/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Codón sin Sentido/genética , Difosfonatos/uso terapéutico , Mutación del Sistema de Lectura/genética , Predisposición Genética a la Enfermedad , Humanos , Osteocondrodisplasias/tratamiento farmacológico , Fosforilación/genética , Transducción de Señal/genéticaRESUMEN
Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFß1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated withERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events.
Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Neoplasias Óseas/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores de Estrógenos/genética , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Wnt-5a/metabolismo , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND: Up to 80% of patients dying from prostate carcinoma have developed bone metastases that are incurable. Castration is commonly used to treat prostate cancer. Although the disease initially responds to androgen blockade strategies, it often becomes castration-resistant (CRPC for Castration Resistant Prostate Cancer). Most of the murine models of mixed lesions derived from prostate cancer cells are androgen sensitive. Thus, we established a new model of CRPC (androgen receptor (AR) negative) that causes mixed lesions in bone. METHODS: PC3 and its derived new cell clone PC3c cells were directly injected into the tibiae of SCID male mice. Tumor growth was analyzed by radiography and histology. Direct effects of conditioned medium of both cell lines were tested on osteoclasts, osteoblasts and osteocytes. RESULTS: We found that PC3c cells induced mixed lesions 10 weeks after intratibial injection. In vitro, PC3c conditioned medium was able to stimulate tartrate resistant acid phosphatase (TRAP)-positive osteoclasts. Osteoprotegerin (OPG) and endothelin-1 (ET1) were highly expressed by PC3c while dikkopf-1 (DKK1) expression was decreased. Finally, PC3c highly expressed bone associated markers osteopontin (OPN), Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP) and produced mineralized matrix in vitro in osteogenic conditions. CONCLUSIONS: We have established a new CRPC cell line as a useful system for modeling human metastatic prostate cancer which presents the mixed phenotype of bone metastases that is commonly observed in prostate cancer patients with advanced disease. This model will help to understand androgen-independent mechanisms involved in the progression of prostate cancer in bone and provides a preclinical model for testing the effects of new treatments for bone metastases.
Asunto(s)
Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Neoplasias de la Próstata/patología , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Remodelación Ósea/genética , Huesos/metabolismo , Huesos/patología , Línea Celular Tumoral , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Masculino , Ratones , Orquiectomía , Osteoblastos/metabolismo , Osteólisis/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugía , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRα) has been implicated in breast cancer and bone development, prompting us to examine whether ERRα may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer, overexpression of wild-type ERRα reduced metastasis, whereas overexpression of a dominant negative mutant promoted metastasis. Osteoclasts were directly affected and ERRα upregulated the osteoclastogenesis inhibitor, osteoprotegerin (OPG), providing a direct mechanistic basis for understanding how ERRα reduced breast cancer cell growth in bone. In contrast, ERRα overexpression increased breast cancer cell growth in the mammary gland. ERRα-overexpressing primary tumors were highly vascularized, consistent with an observed upregulation of angiogenic growth factor, the VEGF. In support of these findings, we documented that elevated expression of ERRα mRNA in breast carcinomas was associated with high expression of OPG and VEGF and with disease progression. In conclusion, our results show that ERRα plays a dual role in breast cancer progression in promoting the local growth of tumor cells, but decreasing metastatic growth of osteolytic lesions in bone.