RESUMO
Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Monócitos , Transdução de Sinais , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Colágeno/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/genética , Monócitos/metabolismo , Monócitos/patologia , Metástase Neoplásica , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals at autopsy. Prolactin-producing adenomas, i.e., prolactinomas, comprise approximately 50% of all pituitary adenomas and represent the most common class of pituitary tumor. Multiple observations suggest that estrogens may contribute to development of prolactinoma; however, direct evidence for a causal role of estrogens in prolactinoma etiology is lacking. Rat models of estrogen-induced prolactinoma have been utilized extensively to identify the factors, pathways and processes that are involved in pituitary tumor development. The objective of this study was to localize to high resolution Ept7 (Estrogen-induced pituitary tumor), a quantitative trait locus (QTL) that controls lactotroph responsiveness to estrogens and was mapped to rat chromosome 7 (RNO7) in an intercross between BN and ACI rats. Data presented and discussed herein localize the Ept7 causal variant(s) to a 1.91 Mb interval of RNO7 that contains two protein coding genes, A1bg and Myc, and Pvt1, which yields multiple non-protein coding transcripts of unknown function. The Ept7 orthologous region in humans is located at 8q24.21 and has been linked in genome wide association studies to risk of 8 distinct epithelial cancers, including breast, ovarian, and endometrial cancers; 3 distinct types of B cell lymphoma; multiple inflammatory and autoimmune diseases; and orofacial cleft defects. In addition, the Ept7 locus in humans has been associated with variation in normal hematologic and development phenotypes, including height. Functional characterization of Ept7 should ultimately enhance our understanding of the genetic etiology of prolactinoma and these other diseases.
Assuntos
Adenoma , Cromossomos de Mamíferos/genética , Estrogênios , Lactotrofos/metabolismo , Neoplasias Hipofisárias , Locos de Características Quantitativas , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Estrogênios/genética , Estrogênios/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hiperplasia , Lactotrofos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , RatosRESUMO
Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17ß-estradiol (E2)-induced mammary cancer is unique among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute ~70% of all breast cancers. E2 drives cancer development in this model through mechanisms that are largely dependent upon estrogen receptors and require progesterone and its receptors. Moreover, mammary cancer development appears to be associated with generation of oxidative stress and can be modified by multiple dietary factors, several of which may attenuate the actions of reactive oxygen species. Studies of susceptible ACI rats and resistant COP or BN rats provide novel insights into the genetic bases of susceptibility and the biological processes regulated by genetic determinants of susceptibility. This review summarizes research progress resulting from use of these physiologically relevant rat models to advance understanding of breast cancer etiology and prevention.
