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

Said, Neveen; Frierson, Henry F.; Chernauskas, D; Conaway, Mark; Motamed, Kouros; Theodorescu, Dan

doi:10.1038/onc.2009.205

Cited by 61 publications

(72 citation statements)

References 55 publications

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“…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.…”

Section: Discussionmentioning

confidence: 90%

“…SPARC plays a significant role in tissue remodeling, maintaining cell matrix integrity and interaction and collagen fiber assembly (34). Stroma-as well as tumor-secreted SPARC is known to affect tumor growth in cell type-and context-dependent manners by regu- lating cell proliferation, adhesion, migration, invasion, and angiogenesis (25,(35)(36)(37)(38). In prostate cancer, apparent conflicting results regarding SPARC expression in both clinical and experimental studies suggest that the role of SPARC is even more complex.…”

Section: Discussionmentioning

confidence: 99%

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

Sharma

Xing

Yin

et al. 2016

Journal of Biological Chemistry

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Prostate cancer is known to frequently recur in bone; however, how dormant cells switch its phenotype leading to recurrent tumor remains poorly understood. We have isolated two syngeneic cell lines (indolent and aggressive) through in vivo selection by implanting PC3mm stem-like cells into tibial bones. We found that indolent cells retained the dormant phenotype, whereas aggressive cells grew rapidly in bone in vivo, and the growth rates of both cells in culture were similar, suggesting a role of the tumor microenvironment in the regulation of dormancy and recurrence. Indolent cells were found to secrete a high level of secreted protein acidic and rich in cysteine (SPARC), which significantly stimulated the expression of BMP7 in bone marrow stromal cells. The secreted BMP7 then kept cancer cells in a dormant state by inducing senescence, reducing "stemness," and activating dormancy-associated p38 MAPK signaling and p21 expression in cancer cells. Importantly, we found that SPARC was epigenetically silenced in aggressive cells by promoter methylation, but 5-azacytidine treatment reactivated the expression. Furthermore, high SPARC promoter methylation negatively correlated with disease-free survival of prostate cancer patients. We also found that the COX2 inhibitor NS398 down-regulated DNMTs and increased expression of SPARC, which led to tumor growth suppression in bone in vivo. These findings suggest that SPARC plays a key role in maintaining the dormancy of prostate cancer cells in the bone microenvironment.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Sharma

Xing

Yin

et al. 2016

Journal of Biological Chemistry

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“…Use of SPARC knockout (Sparc -/-) mice revealed that SPARC suppresses syngeneic and oncogenedriven tumors (9,(11)(12)(13)(14) through regulation of matrix deposition and through antiinflammatory, antiangiogenic, antiproliferative, and proapoptotic effects, while SPARC has been found to be upregulated in the stroma (9,15). SPARC exerts autocrine and paracrine inhibition of cancer cell proliferation through cell-cycle arrest (8,9,13,16,17) and suppression of survival signaling (7,11,12,18,19), cancer cell adhesion, and invasion (8,11,12,17,18).…”

Section: Introductionmentioning

confidence: 99%

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Said¹,

Frierson²,

Sänchez‐Carbayo³

et al. 2013

J. Clin. Invest.

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Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumorand stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

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“…The mechanisms through which Sparcl1 regulates cellular adhesion and migration are not well understood; however, Sparcl1 has been shown to bind type I collagen, a component of the extracellular matrix that potentiates tumor cell migration and invasion (11)(12)(13). Although the C-terminal domain of SPARCL1 is highly homologous to SPARC, an inhibitor of prostate tumorigenesis and progression (14), the relationship of SPARCL1 itself to prostate cancer aggressiveness has not been well characterized.…”

mentioning

confidence: 99%

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

Hurley¹,

Marchionni²,

Simons³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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...

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

Cited by 61 publications

References 55 publications

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

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

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

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

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