Role of MAF in bone metastasis
The identification of genes that mediate metastasis is pivotal to better understand the mechanism, to develop novel drugs and to stratify patients with highest risk and consecutively administrate them preventive treatments. Despite significant advances on knowledge, diagnosis and treatment of cancer...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/482079 |
| Acceso en línea: | http://hdl.handle.net/10803/482079 |
| Access Level: | acceso abierto |
| Palabra clave: | Ossos Huesos Bones Càncer Cáncer Cancer Oncogens Oncogenes Ciències Experimentals i Matemàtiques 616 |
| Sumario: | The identification of genes that mediate metastasis is pivotal to better understand the mechanism, to develop novel drugs and to stratify patients with highest risk and consecutively administrate them preventive treatments. Despite significant advances on knowledge, diagnosis and treatment of cancer, metastasis remains the major cause of cancer-associated deaths. Bone is one of the most common organs affected by metastatic lesions for its permeability and favorable conditions for cellular growth. Constant remodeling in bone homeostasis implies an incessant degradation of the bone that release high concentrations of growth factors into the microenvironment. Thereby, growth factors benefit both, formation of new bone and/or tumor cell growth. Although the importance of bone metastatic lesions in cancer patients and the advances on the knowledge of this process, few treatments are currently administrated to patients that suffer this disease, specifically Denosumab and Zoledronic acid (ZOL). Importantly, these treatments can improve the symptoms of bone lesions but cannot cure or reverse metastasis. This fact reflects the need to detect and tackle new targetable elements to reduce bone metastatic lesions. Many molecular mechanisms have been described in bone metastasis, but only one predictor gene has been identified, MAF. MAF is a transcription factor that has been previously involved in carcinogenesis, specially in multiple myeloma (MM) and human angioimmunoblastic T-cell lymphomas (AITLs). Recently, MAF contribution has been associated for the first time with breast cancer bone metastasis. In this thesis, we determined the role of MAF in several contexts. As a first approach we demonstrated that MAF is also a predictive marker of bone metastasis in prostate cancer (PC) patients. However, regarding androgen-independent PC cell lines, an overexpression of MAF was not enough to drive colonization of the mouse bone. Secondly, we report the beneficial effect of MAF downregulation on preventing skeletal metastasis in BoM2, a highly bone metastatic MCF7-derived cell line. MAF impinged bone colonization in a higher degree that other treatments against bone metastasis, such as PTHrP antagonist or recombinant OPG. This fact identifies MAF as a new potential target to focus on the generation of new drugs. Finally, MAF showed a tendency to redirect metastases to other organs than bone in the presence of ZOL treatment in vivo. Thus, we validated the association between MAF overexpression and an increase on extraskeletal metastases after ZOL preventive treatment in non-postmenopausal BC patients. Moreover, a mouse model was generated to better understand the biology of MAF- derived bone metastasis within complete stromal interactions. We designed a transgenic mouse model to express MAF in the mammary gland in an inducible manner. To this end, we generated two constructs; the first contains rtTA, renilla and katushka under MMTV promoter, and the second contains MAF, luciferase and tGFP under Tet-On promoter. We demonstrated the incorporation of several copy numbers of both transgenes in two independent colonies and we detected transgene expression under doxycycline activation by means of luminescent signal. Even though both colonies incorporated several copy number of the transgene, their expression was soft and some relevant leakiness was observed in the non-treated MAF mice. No differences were observed in terms of mammary gland development between transgene-expressing MAF mice and wild-type mice, as well as no tumor initiation was detected in any group. Notably, MAF Tg mouse was crossed with MMTV-PyMT to generate double Tg mice (PyMT-MAF). PyMT-MAF tumor growth presented no significant differences compared to PyMT in terms of time to tumor formation and growth rate. Importantly, no bone metastases were observed at 3-month-old mice of any group. Thus, the generation of this animal model provided new insights to generate a novel bone metastatic mouse model. |
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