Role of SPARC in bone remodeling and cancer-related bone metastasis

Considerable attempts have been made to produce adequate matrices or scaffolds that mimic bone ECM for applications in tissue engineering and regenerative medicine. In this context, several factors must be considered, such as the modification of biomaterial surfaces using growth factors, living bone cells or proteins, to guide cellular responses in bone remodeling, like osteoblast adhesion and long term functionality expressed as proliferation, synthesis of alkaline phosphatase and deposition of calcium containing mineral. [Manuel et al., 2003] SPARC a matricellular glycoprotein associated with tissue remodeling, repair, development, cell turnover, is involved in bone formation, bone initiating mineralization process and collagen fibril assembly. [Bradshaw et al., 2003; Doi et al., 1989; Kapinas et al., 2012; Termine et al., 1981; Wang et al., 2005] The application of this protein could benefit the development of new valid therapeutic strategies for skeletal tissue regeneration. In addition, the research in this topic is essential since there are very few works involving SPARC and biomaterials for bone tissue regeneration. [Liao et al., 2009; Sarvestani et al., 2008] Furthermore, SPARC controls important mechanisms involved in cancer development and progression including the regulation of epithelial-to-mesenchymal transition, apoptosis, angiogenesis and also the regulation of the inflammatory response. SPARC is relevant in metastatic dissemination capacity of prostate, breast, lung, kidney, thyroid cancer and multiple myeloma cancer cells into bone tissue. Yet, the actual function of SPARC in tumorigenesis and tumor progression is still contradictory and not fully understood. There isn’t any review article addressing SPARC and cancer related bone metastasis. Depending on cancer type, different expression patterns and activities of SPARC may be found. This could be explained by the distinct tumor microenvironment established in different types of cancers that translates in terms of local 11 composition of matrix molecules and cytokines and the protease profile. The different proteolytic products (peptide fragments) corresponding to different regions of SPARC have distinct activities and may explain the divergent and inconsistent biological activities observed with native full-size SPARC protein in distinct malignancies. SPARC peptide models could be a valid strategy to understand SPARC’s specific action in mechanisms that occur in tumor invasion and metastasis in bone tissue. Very few attempts, including SPARC peptides combined with chemotherapy and/or drugs, have been performed in this direction up to now. [Chlenski et al., 2010; Chlenski et al., 2004; Gradishar et al., 2005; Inoue et al., 2010; Von Hoff, 2008] Furthermore the differential function of SPARC in several types of cancers might be dependent upon whether it is expressed by the malignant cells themselves or by neighboring stromal cells. A series of studies have been performed in an attempt to elucidate the actual role of SPARC produced by non-malignant stromal cells. [Brekken et al., 2003; Haber et al., 2008; Sangaletti et al., 2003] SPARC knock-out mice showed low turnover osteopenia [Nie and Sage, 2009], intensive osteoclastogenesis [McCabe et al., 2011] and matrices composed by thinner collagen fibers in random networks [Kapinas et al., 2012] that translated a less stroma and collagen deposition. It was proposed that SPARC is a critical component in the orchestration of the tissue microenvironment, important for metastatic cancer cells to grow and survive in the skeleton (skeletal cancer metastasis). In fact, the expression of many bone-enriched proteins, including SPARC by stromal cells in normal prostate and the up-regulation of VEGF production by SPARC being a prostate cancer specific phenomenon, contributes to the preference and significant growth advantage in bone-like environment by prostate cancer cells. Also the association between SPARC expression pattern and malignancy of prostate and breast cancers may contribute to the use of SPARC as a potential prognostic biomarker of tumor severity and/or metastasis. [DeRosa et al., 2012; Wong et al., 2008] According to the works related to bone metastasis and presented in table 1, SPARC acts as protumorigenic and prometastatic protein, when expressed by stromal cells, trough enhancement of metalloprotease activity, VEGF production, or chemoattraction toward vitronectin. [Chen et al., 2007; De et al., 2003; DeRosa et al.,

Autores e afiliações:
N. Ribeiro1,2, S.R. Sousa1,3, R.A. Brekken4, F.J. Monteiro1,2

1 INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre, 823,4150-180 Porto, Portugal

2 Universidade do Porto, Faculdade de Engenharia, Departamento de Engenharia Metalúrgica e de Materiais, Rua Roberto Frias, 4200-465 Porto, Portugal

3 REQUIMTE, ISEP - Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida, 431, 4200-072 Porto, Portugal

4 UT Departments of Surgery and Pharmacology and the Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center 6000 Harry Hines Blvd. MC8593 Dallas, TX 75390-8593

Abstract:

There is a growing socioeconomic recognition that clinical bone diseases such as bone infections, bone tumors and osteoporotic bone loss mainly associated with ageing, are major issues in today’s society. SPARC (secreted protein, acidic and rich in cysteine), a matricellular glycoprotein, may be a promising therapeutic target for preventing or treating bone related diseases. In fact, SPARC is associated with tissue remodeling, repair, development, cell turnover, bone mineralization and may also participate in growth and progression of tumors, namely cancer-related bone metastasis. Yet, the function of SPARC in such biological processes is poorly understood and controversial. The main objective of this work is to review the current knowledge related to the activity of SPARC in bone remodeling, tumorigenesis and bone metastasis. Progress in understanding SPARC biology may provide novel strategies for bone regeneration and the development of anti-angiogenic, anti-proliferative or counter-adhesive treatments specifically against bone metastasis.

Revista:
Journal of Cellular Biochemistry

Link:
http://onlinelibrary.wiley.com/doi/10.1002/jcb.24649/pdf doi: [10.1002/jcb.24649]