5q31.3-q32

BM-40,OI17,ON,ONT

Osteogenesis Imperfecta, Type XVII

SPARC gene mutations have been correlated with a severe disease known as osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Whole-exome sequencing was carried out in 2 unrelated girls carrying osteogenesis imperfecta (OI17; 616507) leading to the identification of two different homozygous missense mutations, R166H (VAR_075142) and E263K (VAR_075143) (Mendoza-Londono et al., 2015). Previous studies described diminished expression of SPARC in osteoblasts from patients with osteogenesis imperfecta (Muriel et al., 1991) and in osteoblasts obtained from the fro/fro mouse, an animal with fragile bones (Vetter et al., 1991)

Osteoporosis

The involvement of SPARC in bone remodeling has been described, and its expression is observed in osteoblasts express (Kelm et al., 1992). SPARC-null mice were reported to have decreased numbers of osteoblasts and osteoclasts, indicating decreased bone turnover, resulting in low turnover osteoporosis-like phenotype affecting trabecular bone (Delany, et al., 2000). Also, in osteonectin-null mice, osteonectin levels have been shown to play a role in modulating the balance of bone formation and resorption in response to PTH treatment (Machado do Reis et al., 2008).

Pulmonary and Cardiac Fibrosis

Fibrosis is characterized by excessive deposition of extracellular matrix, resulting in tissue remodeling and thus interfering with normal tissue architecture and function.
SPARC expression and up-regulation have been reported in multiple types of fibrosis both human and animal fibrotic models. It has been shown that SPARC can influence TGFB1 (TGF-beta), a known regulator of fibrosis. Thus it is suggested that SPARC may regulate TGF-beta activity in fibrotic tissues (Trombetta and Bradshaw, 2012).

Cardiac disease

SPARC expression was reported in cardiac disease. It is highly expressed in fibroblasts and endothelial cells and less expressed in cardiac myocytes. By screening analysis, SPARC was found as differentially expressed and potentially associated with myocardial infarction and transverse aortic constriction (Wang et al., 2015). Also, SPARC demonstrated to have potential therapeutic applications in inhibiting cardiac dilatation and dysfunction after myocardial infarction (Schelling et al., 2009).

Cancer

SPARC protein modulates different cell functions like as adhesion, proliferation, angiogenesis, cell survival, and has been associated with tumor development and progression (Arnold and Brekken, 2009; Nagaraju et al., 2014).
SPARC is differentially expressed in different types of cancer, and its ability to inhibit or promote tumor progression is dependent on the cellular type, tumoral stage and the type of established interactions among the different components of cellular microenvironment (Arnold and Brekken, 2009).
The pleiotropic effects of SPARC reflect the complexity of actions of this protein, which can act as an oncogene or tumor suppressor (Podhajcer et al.,2008; Arnold and Brekken, 2009). Hence, the role of SPARC in the process of tumorigenesis and as a tumor biomarker is still controversial. Higher levels of SPARC were observed in malignant tumors, including breast, esophagus, brain, prostate, glioma, and melanoma, suggesting that increased SPARC expression is associated with tumor progression (Framson and Sage, 2004; Bos et al.,2004; Watkins et al.,2005; Koblinski et al.,2005). On the other hands, other studies have suggested that SPARC may act as a tumor suppressor, promoting apoptosis in ovarian cancer cells and presenting an anti-tumoral effect in pancreatic and breast cancers (Chlenski and Cohn, 2010; Nagai et al.,2011).
Tumor with high metastatic potentials such as glioblastomas, melanoma, breast and prostate cancer, express higher levels of SPARC while less metastatic tumor-like ovarian, pancreatic and colorectal tumors, expresses lower or undetectable SPARC (Feng and Tang, 2014).
The diversity of SPARC expression effects has been observed in different types of cancers. SPARC has been associated with tumor development in melanoma, esophagus cancer, gastric cancer and glioma, and data suggests that higher expression is correlated with a more aggressive phenotype such as tumor size, metastasis and poor prognosis (Yamashita K et al., 2003; Bos et al.,2004; Framson and Sage, 2004; Wang  et al., 2004; Koblinsk et al.,2005; Zhao et al., 2010; Fenouille et al., 2011; Liu et al., 2011; Rocco et al., 2011; McClung et al., 2012; Kim et al., 2013) The expression of SPARC does not seem to directly influence cellular transformation since SPARC knockout mice do not develop tumors. However, SPARC might significantly influence tumor-stroma interactions contributing to tumor progression and therapy response (Said et al., 2013).
In different tumor types such as prostatic carcinoma, neuroblastoma, pulmonary carcinoma, leukemia, pancreatic and colorectal cancer, it was described that SPARC inhibits tumor growth and reverts drug resistance increasing chemotherapy response. (Brekken et al., 2003; Sato et al., 2003; Puolakkainen et al., 2004; Said and Motamed, 2005; Tai et al., 2005; DiMartino et al., 2006; Tai and Tang, 2007; Cheetam et al., 2008; Pan et al., 2008; Wong et al., 2008; Socha et al., 2009; Bhoopathi et al., 2011; Davids and Steensma, 2010; Chew et al., 2011; Rahman et al., 2011).
Cheetham et al., 2008, showed that the demethylating agent 5-Aza-2deoxycytidine (5-Aza) leads to the expression of SPARC and increased chemosensitivity in colon cancer cells. In irinotecan-resistant cancer cells, endogenous or exogenous SPARC exposure triggers senescence associated with increased levels of p16 and TP53 phosphorylation (Chan et al., 2010). Also, in vitro and in vivo studies have demonstrated that over-expression of the NT-domain of SPARC leads to a significantly greater sensitivity to chemotherapy and tumor regression that involves an interplay between the NT-domain, BCL2 and CASP8 (caspase 8), which increases apoptosis and confers greater chemosensitivity (Rahman et al., 2011). More recently, Fan et al., demonstrated that over-expression of SPARC increased gemcitabine-induced apoptosis in pancreatic cancer cells via up-regulation of the expression of apoptosis-related proteins. These findings provide insight on the role played by SPARC in drug sensitivity and that its re-expression has a potential to restore chemosensitivity.

Breast cancer

In breast cancer, SPARC is expressed in more invasive but not in non-invasive cell lines (Giles et al., 1998). In normal mammary tissue, SPARC expression was undetectable or slightly detectable and in benign mammary lesions the expression was weakly positive. However, the stromal cell of 75% of in situ and invasive breast cancer samples was strongly positive for SPARC (Bellahcène and Castronovo, 1995; Barth et al., 2005; Matteucci et al., 2016).
As previous described, the role of SPARC in breast cancer is also controversial. SPARC expression is not detected in MCF-7 breast cancer cell line, however, in response to c-Jun overexpression, SPARC expression is highly induced being associated to increased invasive and migration potential (Briggs et al., 2002). Instead, in the tumorigenic model of breast cancer cells, MDA-MD-231, SPARC expression inhibited invasion and metastasis (Koblinski et al., 2005).
In breast tumors increased SPARC expression was associated with tumor progression and aggressiveness phenotype (Watkins et al., 2005 and Helleman et al. 2008). On the other hand, the reduction of SPARC protein expression was associated with poor prognosis of breast cancer patients (Hsiao et al., 2010 e Nagai et al., 2011). In breast cancer brain metastasis SPARC expression was down-regulated in comparison to primary tumors, apart from the tumoral subtype. However, among the primary tumors evaluated, triple negative subtype expressed the higher protein level (Wikman et al., 2014). Previous data of our group, have already shown that association between SPARC and triple negative tumors, and positivity to SPARC was a marker of good prognosis in comparison to those patients with reduced SPARC level (Nagai et al., 2011).