Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM

Brekken, Rolf A.; Puolakkainen, Pauli; Graves, David C.; Workman, Gail; Lubkin, Sharon R.; Sage, E. Helene

doi:10.1172/jci200316804

Cited by 90 publications

(135 citation statements)

References 40 publications

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“…Interestingly, the tumors that develop in SPARC null mice exhibit significant alterations in the production and organization of the extracellular matrix components, and these changes are believed to create a permissive environment for the accelerated tumor growth and invasion of cancer cells (Brekken et al, 2003). Our study supports the concept that SPARC influences tumor growth by regulating tumor stroma assembly.…”

Section: Discussionsupporting

confidence: 78%

SPARC enhances tumor stroma formation and prevents fibroblast activation

et al. 2007

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Tumor growth is influenced by interactions between malignant cells and the tumor stroma. Although the normal host microenvironment is nonpermissive for neoplastic progression, tumor-reactive stroma, characterized by the presence of activated fibroblasts, promotes neoplastic growth and metastasis. Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is capable of inhibiting the growth of several different types of cancer. Recently, we reported that SPARC also impairs the growth of xenografts comprised of 293 cells. In this study, we show that in addition to enhancing stroma formation, SPARC prevents fibroblast activation in 293 xenografts, suggesting that the anticancer effects of SPARC may be due, at least in part, to the formation of tumor stroma that is not supportive of tumor growth. In vitro, 3T3 fibroblasts cocultured with SPARC-transfected 293 cells remain negative for a-smooth muscle actin, whereas wild-type 293 cells induce fibroblast activation. Moreover, activation of 3T3 cells and primary fibroblasts by transforming growth factor b is blocked by SPARC treatment. We also demonstrate that SPARC significantly increases basic fibroblast growth factor-induced fibroblast migration in vitro, indicating that it may recruit host fibroblasts to the tumor stroma. Taken together, our results suggest that in addition to blocking angiogenesis, SPARC may inhibit tumor growth by promoting the assembly of stroma that is nonpermissive for tumor progression.

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Section: Discussionsupporting

confidence: 78%

SPARC enhances tumor stroma formation and prevents fibroblast activation

et al. 2007

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“…Murine pancreatic cancer cells injected orthotopically into SPARC-null mice grow larger and metastasize more frequently than those in wild-type mice, thus highlighting the importance of SPARC function and ECM composition in tumor progression (Arnold et al, 2008). The fact that the tumor cells, but not the infiltrating stroma cells, express and secrete SPARC in the aforementioned studies also supports the observation that the effect of SPARC on tumorigenesis is context-and cell-type dependent (Brekken et al, 2003;Puolakkainen et al, 2004).…”

Section: Discussionmentioning

confidence: 63%

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

et al. 2011

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Tumor protein 53 induced nuclear protein 1 (TP53INP1) is a p53 target gene that induces cell growth arrest and apoptosis by modulating p53 transcriptional activity. TP53INP1 interacts physically with p53 and is a major player in the p53-driven oxidative stress response. Previously, we demonstrated that TP53INP1 is downregulated in an early stage of pancreatic cancerogenesis and when restored is able to suppress pancreatic tumor development. TP53INP1 downregulation in pancreas is associated with an oncogenic microRNA miR-155. In the present work, we studied the effects of TP53INP1 on cell migration. We found that TP53INP1 inactivation correlates with increased cell migration both in vivo and in vitro. The impact of TP53INP1 expression on cell migration was studied in different cellular contexts: mouse embryonic fibroblast and different pancreatic cancer cell lines. Its expression decreases cell migration by the transcriptional downregulation of secreted protein acidic and rich in cysteine (SPARC). SPARC is a matrix cellular protein, which governs diverse cellular functions and has a pivotal role in regulating cell-matrix interactions, cellular proliferation and migration. SPARC was also showed to be upregulated in normal pancreas and in pancreatic intraepithelial neoplasia lesions in a pancreatic adenocarcinoma mouse model only in the TP53INP1-deficient animals. This novel TP53INP1 activity on the regulation of SPARC expression could explain in part its tumor suppressor function in pancreatic adenocarcinoma by modulating cellular spreading during the metastatic process.

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“…23 Several lines of evidence suggest a tumor-suppressor role of SPARC in certain tumor types. [62][63][64][65] We have recently demonstrated that stromal SPARC patterns independently predict outcome in patients with pancreatic ductal adenocarcinoma. 66 SARP2 is an apoptosis-related gene that interacts the Wnt oncogenic signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P ¼ 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P ¼ 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P ¼ 0.001), Reprimo (P ¼ 0.01), and LHX1 (P ¼ 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression. Keywords: PanIN; pancreatic cancer; methylation specific PCR; DNA methylation Accumulating evidence supports the hypothesis that infiltrating adenocarcinoma of the pancreas develops from noninvasive precursor lesions in the small ducts and ductules, called pancreatic intraductal neoplasia (PanIN). 1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions. The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristi...

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Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM

Cited by 90 publications

References 40 publications

SPARC enhances tumor stroma formation and prevents fibroblast activation

SPARC enhances tumor stroma formation and prevents fibroblast activation

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

CpG island methylation profile of pancreatic intraepithelial neoplasia

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