The high stromal SPARC expression is independently associated with poor survival of patients with resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine in combination with S-1 or adjuvant gemcitabine alone

Shintakuya, Ryuta; Kondo, Naru; Murakami, Yoshiaki; Uemura, Kenichiro; Nakagawa, Noritoshi; Okano, Keisuke; Takahashi, Shinya; Sueda, Taijiro

doi:10.1016/j.pan.2017.12.014

Cited by 10 publications

(9 citation statements)

References 27 publications

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“…This is in line with higher stromal SPARC abundance in stage II-IV CRC as compared to stage I [25] and with the association of high stromal SPARC with shorter survival in recurrent disease. As such, our study is the first that associates stromal SPARC with tumor progression and poor outcome in CRC based on both patient and in vitro data, which is well in line with recent reports from pancreatic, gastric and biliary cancer that all identify stromal SPARC as a predictor of worse survival [45,46,47]. For CRC, stromal SPARC seems to be a conditional predictor that only exerts a strong impact in recurrent disease.…”

Section: Discussionsupporting

confidence: 88%

Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells

Drev

Harpain

Beer

et al. 2019

Cancers

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Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC expression in patients suffering from stage II and III CRC using a publicly available mRNA data set and immunohistochemistry of tissue microarray sections. Moreover, in vitro co-culture models using CRC cell lines together with colon-associated fibroblasts were established to determine the effect of fibroblast-derived SPARC on cancer cells. In 466 patient samples, high SPARC mRNA was associated with a shorter disease-free survival. In 99 patients of the tissue microarray cohort, high stromal SPARC in the primary tumor was an independent predictor of shorter survival in patients with relapse (27 cases; HR = 4574, p = 0.004). In CRC cell lines, SPARC suppressed phosphorylation of focal adhesion kinase and stimulated cell migration. Colon-associated fibroblasts increased migration velocity by 30% and doubled track-length in SPARC-dependent manner. In a 3D co-culture system, fibroblast-derived SPARC enhanced tumor cell invasion. Taken together, stromal SPARC had a pro-metastatic impact in vitro and was a characteristic of aggressive tumors with poor prognosis in CRC patients.

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Section: Discussionsupporting

confidence: 88%

Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells

Drev

Harpain

Beer

et al. 2019

Cancers

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“…Shintakuya et al also reported that high expression of SPARC in the peripheral stroma independently predicts poor disease-free survival (hazard ratio [HR] 1.72, 95%CI 1.12-2.68; P=0.013) and overall survival (HR 3.34, 95%CI 2.11-5.51; P<0.001) in PAC patients. They analyzed cytoplasmic and stromal SPARC expression in 211 patients who underwent curative resection and were treated with either gemcitabine + S-1 or gemcitabine alone, and discovered a high stromal SPARC expression in 59.2% of cases and a high cytoplasmic SPARC expression in 26.1% of cases, but only stromal and not cytoplasmic expression of SPARC predicted disease-free and overall survival in PAC patients [27]. Gundewar et al published similar results after studying SPARC stromal expression in 88 PAC cases.…”

Section: Discussionmentioning

confidence: 99%

“…However, in this Swedish study, SPARC expression was positive in a higher percentage, i.e., 77.3%, when compared to expression reported in Japanese populations, i.e.,. 39-59% [26][27][28]. Infante et al studied SPARC expression in the tumor stroma of 299 PAC patients who underwent surgical resection and found 200 (67%) stroma-positive cases.…”

Section: Discussionmentioning

confidence: 99%

Temporal trends of incidence and mortality in Asian-Americans with pancreatic adenocarcinoma: an epidemiological study

Gad

Găman

Saad

et al. 2020

aog

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Background Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with an estimated 45,750 deaths in 2019. Mortality outcomes seem to differ based on the ethnicity of the patients, with most studies focusing on the mortality and survival of Caucasians and African Americans. Little attention has been given, however, to Asian-American patients diagnosed with pancreatic adenocarcinoma (PAC). In this study, we aimed to investigate mortality rates in Asian-American patients with PAC. Methods The SEER 13 registries (Surveillance, Epidemiology, and End-Results) of the National Cancer Institute were used to study PAC cases during 1992-2015. The incidence and incidencebased mortality rates per 100,000 person-years, and the annual percentage changes were calculated using SEER*stat software and Joinpoint regression software. Results A total of 5814 PAC cases in Asian-American patients were identified. Most patients were older than 60 years (77.6%) and had metastatic disease (55.8%). The overall incidence of PAC among Asian-Americans was 5.740 per 100,000 person-years (95% confidence interval [CI] 5.592-5.891]. Incidence rates were highest among males and patients older than 60 years. PAC incidence rates among Asian-Americans increased by 1.503% (95%CI 1.051-1.956; P<0.001) per year over the study period. PAC incidence rates increased over the study period for all sex, age, and stage subgroups. PAC incidence-based mortality among Asian-Americans increased by 4.535% (95%CI 3.538-5.541; P<0.001) per year over the study period. Conclusion The incidence of PAC in Asian-Americans, as well as incidence-based mortality rates, are on the rise, irrespective of age, sex or stage subgroup.

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“…SPARC is a stroma-derived protein that plays a critical role in this desmoplastic response [3]. High SPARC expression is strongly associated with poor patient prognosis in resectable and locally advanced pancreatic cancer [4][5][6][7][8]. Furthermore, it is clear that while SPARC is normally expressed at low levels in adult tissues, pancreatic tumours commonly express high levels of SPARC [9,10].…”

Section: Introductionmentioning

confidence: 99%

Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein SPARC has been robustly associated with poor patient prognosis. However, the precise role of SPARC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein in vitro. This conflicting data has been a barrier to the development of new therapeutic approaches targeting SPARC, despite current interest in stromal-therapy.We show conclusively that SPARC acts directly on cancer cells to promote pancreatic cancer cell proliferation. This contradicts previous in vitro studies, but is consistent with the observed clinical association between SPARC expression and poor patient prognosis. However, depletion of fibronectin switches the activity of SPARC from promoting cancer cell proliferation to growth inhibition and induction of apoptosis. Thus, targeting the interaction between SPARC and fibronectin could be used to turn the highly expressed tumour protein SPARC against the tumour to induce tumour cytotoxicity, and is a novel target for PDAC therapy.

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The high stromal SPARC expression is independently associated with poor survival of patients with resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine in combination with S-1 or adjuvant gemcitabine alone

Cited by 10 publications

References 27 publications

Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells

Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells

Temporal trends of incidence and mortality in Asian-Americans with pancreatic adenocarcinoma: an epidemiological study

Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer

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