Analyses of the role of endogenous SPARC in mouse models of prostate and breast cancer

Abstract

Secreted protein, acidic and rich in cysteine (SPARC, also known as osteonectin or BM-40) is a glycoprotein component of the extracellular matrix that has been reported to be involved with a variety of cellular processes. Although SPARC expression levels are frequently altered in a variety of tumor types, the exact implications of deregulated SPARC expression--whether it promotes, inhibits or has no effect on tumor progression--have remained unclear. Our recent gene expression analyses have shown that SPARC is significantly downregulated in highly metastatic human prostate cancer cells. To test the role of endogenous SPARC in tumorigenesis directly, we examined cancer progression and metastasis in SPARC(+/-) and SPARC(-/-) mice using two separate transgenic mouse tumor models: transgenic adenocarcinoma of the mouse prostate (TRAMP) and murine mammary tumor virus-polyoma middle T (MMTV-PyMT). Surprisingly, in both instances, we found that loss of SPARC had no significant effects on tumor initiation, progression or metastasis. Tumor angiogenesis and collagen deposition were also largely unaffected. Our results indicate that, although differential SPARC expression may be a useful marker of aggressive, metastasis-prone tumors, loss of SPARC is not sufficient either to promote or to inhibit cancer progression in two spontaneous mouse tumor models.

The role of SPARC in the TRAMP model of prostate carcinogenesis and progression

“…These findings are in accord with the reports describing the decreased SPARC expression in primary prostate tumors compared to normal prostates and secondary metastatic sites (Thomas et al, 2000;Wong et al, 2008), and also parallel the reported differential expression of SPARC and its regulator p45-sErb3 (Chen et al, 2007).…”

“…To determine if SPARC exerts similar effects on human prostate cancer, we used human prostate cancer cell lines, DU145, PC3 and LNCaP (with low, absent or detectable endogenous SPARC respectively; Thomas et al, 2000;Wang et al, 2005;Wong et al, 2008) and transiently transfected them with pSPARC. Western blot analysis of cell-cycle regulatory proteins revealed that transient overexpression of pSPARC decreased expression of cyclins A and D1 concomitant with upregulation of p21 Cip and p27 kip ( Figure 2c).…”

“…Gene expression array data of clinical samples from prostate cancer patients corroborate (Dhanasekaran et al, 2001;Lapointe et al, 2004;Tomlins et al, 2007) this finding. In addition, low or absent SPARC expression has been reported in metastatic human prostate cancer cell lines DU145, PC3 and their more aggressive derivatives Wong et al, 2008). Recently, an interaction between prostate cancer cells and bone has been proposed as a potential explanation for the tropic nature of metastasis of prostate cancer to bone (Chen et al, 2007).…”

“…For example, SP À/À mice were shown to be resistant to UV irradiation-induced squamous cell carcinomas (Aycock et al, 2004) and APC Min/ þ -induced spontaneous intestinal adenomas, relative to SP þ / þ animals (Sansom et al, 2007). The role of endogenous SPARC in spontaneous carcinogenesis and metastasis has been studied by comparing SP þ /À and SP À/À mice interbred with transgenic adenocarcinoma of mouse prostate (TRAMP) or murine mammary tumor viruspolyoma middle T (Wong et al, 2008). In this study, mice lacking SPARC expression were compared to those heterozygous for SPARC in a mixed genetic background.…”

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…Moreover, the controversy of the pathological role of SPARC in prostate cancer was further affirmed in two separate studies that utilized the SPARC knockout and transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse models. Although Said et al (25) found an inhibitory role of SPARC in tumor and metastatic growth, another study did not identify any role of SPARC in tumor progression and metastasis (49). The discrepancy in the pathological outcome evident in these studies might be due to the differences in genetic background of the mice used in the study.…”