Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

Abstract

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.Hevin | synaptic cleft 1 | urogenital sinus | extracellular matrix P rostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in United States men. Controversy currently exists over the best treatment strategy for men with high-risk disease (clinical stage ≥T2c, Gleason score 8-10 or prostate-specific antigen > 20 ng/mL) because 56-65% of these men recur after definitive local therapy (1-5). This finding highlights the need for a better understanding of the biologic determinants driving disease progression for both prognostic and therapeutic development.We and others have recently illustrated that pathways essential for prostate organogenesis are reactivated in prostate cancer (6, 7). During organogenesis, androgens induce epithelialmesenchymal interactions in the urogenital sinus (UGS) and drive its differentiation into a prostate (8). We examined early prostate organogenesis shortly after initial androgen exposure, when urogenital sinus epithelia (UGE) migrate and invade into the surrounding mesenchyme and determined that the genes defining this developmental stage were similarly regulated in the transition between low-and high-grade prostate cancers (6). Among these genes, SPARCL1 (SPARC-like 1/Hevin/SC1), a member of the secreted protein, acidic and rich in cysteine (SPARC) family of matricellular proteins, was down-regulated specifically during embryoni...

Clinicopathological Significance of Reduced SPARCL1 Expression in Human Breast Cancer

“…The result indicates that SPARCL1 expression is negatively related to the malignant biological behavior of breast carcinogenesis. It is supposed that SPARCL1 may inhibit tumor growth and progression which has been confirmed by the findings with respect to SPARCL1 in prostate cancer (Hurley et al, 2012) and pancreatic cancer (Esposito et al, 2007).…”

“…In the growth and proliferation of various tumor cells, SPARCL1 often presents decreased expression as a negative regulative factor, which may be closely related to the increase of the cell proliferation activity and the cell cycle progression (Claeskens et al, 2000). Particularly, growing evidence shows that SPARCL1 often presents a reduced or absent expression pattern in a variety of human tumor tissues (Bendik et al, 1998;Nelson et al, 1998;Isler et al, 2004;Esposito et al, 2007;Zaravinos et al, 2011;Hurley et al, 2012;Li et al, 2012). However, several studies have also found that an increased expression of SPARCL1 in a few of other type of human tumors derived from liver (Lau et al, 2006), uterus (Mencalha et al, 2008), and colon and rectum (Zhang et al, 2011;Hu et al, 2012).…”

“…SPARCL1 is expressed in many tissues and organs such as heart, lung, brain, bone, muscle, colon and lymphatic gland, but it has a lower expression in pancreas, spleen, thyroid gland and placental tissue and even SPARCL1 is not expressed in liver, kidney and peripheral blood leucocytes (Girard and Springer, 1995;Hambrock et al, 2003). Recently, a few of studies have reported that SPARCL1 was down-regulated in a wide variety of human malignancies including lung cancer (Bendik et al, 1998;Isler et al, 2004), prostate cancer (Nelson et al, 1998;Hurley et al, 2012), pancreatic cancer (Esposito et al, 2007), and gastric cancer (Li et al, 2012), and might play a role as a tumor suppressor gene (Claeskens et al, 2000). However, little is known about the expression and significance of SPARCL1 in human breast cancer.…”

Matricellular protein SPARCL1 regulates tumor microenvironment–dependent endothelial cell heterogeneity in colorectal carcinoma

“…SPARCL1 is a member of the SPARC family of secreted matricellular proteins, together with SPARC/osteonectin, SMOCs, testicans, and follistatin-like protein 1 (37). SPARCL1 was shown to be a tumor suppressor in various cancers such as CRC (24), pancreatic cancer (54), and prostate cancer (55). SPARCL1 inhibits EC adhesion and spreading (38), but its direct impact on EC proliferation, migration, and capillary morphogenesis has not been investigated.…”

“…Specifically in CRC, the quiescence-inducing activity of SPARCL1 may contribute to the angiostatic micromilieu associated with a Th1-TME. In addition, SPARCL1 is secreted, and inhibitory effects on different tumor cell lines have been reported (24,54,55). Accordingly, SPARCL1 may be among the first EC-derived proteins with antitumorigenic activity, contributing to the positive prognosis associated with a Th1-TME.…”