α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal Adenocarcinoma

Fujita, Hayato; Ohuchida, Kenoki; Mizumoto, Kazuhiro; Nakata, Kohei; Yu, Jun; Kayashima, Tadashi; Chen, Lin; Manabe, Tatsuya; Ohtsuka, Takao; Tanaka, Masao

doi:10.1097/mpa.0b013e3181dbf647

Cited by 100 publications

(86 citation statements)

References 49 publications

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“…However, the combined pericyte signature at the mRNA level was much more effective at predicting relapse (P ¼ 0.00067) than the level of aSMA staining (P ¼ 0.03691). High aSMA protein has also been reported to be of prognostic value in colorectal cancer (7) and at the mRNA level in pancreatic adenocarcinoma (8,46). In contrast, recent studies in murine models of pancreatic adenocarcinoma provide evidence in favor of aSMA þ cells having a role in limiting tumor growth and metastasis by either suppressing immune surveillance (47) or perhaps decreasing tumor angiogenesis (48).…”

Section: Discussionmentioning

confidence: 87%

“…Stromal signatures strongly predict relapse in ovarian, colorectal, pancreatic, and breast cancers (5)(6)(7)(8)(9), contributing to the prevailing view that the TME is pro-tumorigenic. Although sufficient evidence exists to support the notion that recruitment of a cooperative stroma is essential for malignant progression, it is equally plausible that the influx of some stromal elements is the body's attempt to limit cancer spread through fibroblastic encapsulation typical of many tumor types.…”

Section: Introductionmentioning

confidence: 99%

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Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients

Sinha

Chong

George

et al. 2016

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the role of pericytes in regulating malignant ovarian cancer progression.Experimental Design: The pericyte mRNA signature was used to interrogate ovarian cancer patient datasets to determine its prognostic value for recurrence and mortality. Xenograft models of ovarian cancer were used to determine if co-injection with pericytes affected tumor growth rate and metastasis, whereas coculture models were utilized to investigate the direct effect of pericytes on ovarian cancer cells. Pericyte markers were used to stain patient tissue samples to ascertain their use in prognosis.Results: Interrogation of two serous ovarian cancer patient datasets [the Australian Ovarian Cancer Study, n ¼ 215; and the NCI TCGA (The Cancer Genome Atlas), n ¼ 408] showed that a high pericyte score is highly predictive for poor patient prognosis. Co-injection of ovarian cancer (OVCAR-5 & -8) cells withpericytes in a xenograft model resulted in accelerated ovarian tumor growth, and aggressive metastases, without altering tumor vasculature. Pericyte co-culture in vitro promoted ovarian cancer cell proliferation and invasion. High aSMA protein levels in patient tissue microarrays were correlated with more aggressive disease and earlier recurrence.Conclusions: High pericyte score provides the best means to date of identifying patients with ovarian cancer at high risk of rapid relapse and mortality (mean progression-free survival time < 9 months). The stroma contains rare yet extremely potent locally resident mesenchymal stem cells-a subset of "cancer-associated fibroblasts" that promote aggressive tumor growth and metastatic dissemination, underlying the prognostic capacity of a high pericyte score to strongly predict earlier relapse and mortality.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients

Sinha

Chong

George

et al. 2016

Clinical Cancer Research

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“…[31][32][33][34][35][36] In addition, the detection of pancreatic stellate cells immediately adjacent to pancreatic ductal adenocarcinoma epithelium correlates with adverse clinicopathological parameters. 6,7,37 Our group and others have shown that highly contractile pancreatic stellate cells can produce aligned collagen matrices in vitro, and the resultant topography can facilitate pancreatic ductal adenocarcinoma cancer cell migration. [38][39][40] Our immunohistochemical analysis suggests a positive correlation between alpha-smooth muscle actin expression and aligned collagen in the pancreatic ductal adenocarcinoma periductal stroma, which should be further validated on a larger patient cohort for potential mechanistic insight (Figure 4, Supplementary Figure S3).…”

Section: Discussionmentioning

confidence: 99%

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

et al. 2015

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Pancreatic ductal adenocarcinoma continues to be one of the most difficult diseases to manage with one of the highest cancer mortality rates. This is due to several factors including nonspecific symptomatology and subsequent diagnosis at an advanced stage, aggressive metastatic behavior that is incompletely understood, and limited response to current therapeutic regimens. As in other cancers, there is great interest in studying the role of the tumor microenvironment in pancreatic ductal adenocarcinoma and whether components of this environment could serve as research and therapeutic targets. In particular, attention has turned toward the desmoplastic collagen-rich pancreatic ductal adenocarcinoma stroma for both biological and clinical insight. In this study, we used quantitative second harmonic generation microscopy to investigate stromal collagen organization and structure in human pancreatic ductal adenocarcinoma pathology tissues compared with non-neoplastic tissues. Collagen topology was characterized in whole-tissue microarray cores and at specific pathology-annotated epithelial-stroma interfaces representing 241 and 117 patients, respectively. We quantitatively demonstrate that a unique collagen topology exists in the periductal pancreatic ductal adenocarcinoma stroma. Specifically, collagen around malignant ducts shows increased alignment, length, and width compared with normal ducts and benign ducts in a chronic pancreatitis background. These findings indicate that second harmonic generation imaging can provide quantitative information about fibrosis that complements traditional histopathologic insights and can serve as a rich field for investigation into pathogenic and clinical implications of reorganized collagen as a pancreatic ductal adenocarcinoma disease marker. Pancreatic ductal adenocarcinoma is one of the most devastating human malignancies. It is currently the fourth leading cause of cancer death and projects to become the second leading cause by 2030. 1 The 5-year relative survival rate has remained in the single digits for decades. Pancreatic ductal adenocarcinoma is notoriously difficult to detect before an advanced, inoperable stage is reached due to nonspecific symptomatology and the retroperitoneal location of the pancreas, which makes palpation or routine biopsy of suspicious masses difficult. Recent advances in the sensitivity and specificity of preoperative imaging modalities such as computer tomography, magnetic resonance imaging, positron emission tomography, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography have played an important role in enhancing pancreatic ductal adenocarcinoma diagnosis, detailing the relationship of lesions to nearby anatomical structures, and determining the course of management. 2 Despite these advances, only 10-15% of patients are diagnosed at a localized disease stage when surgical resection is possible as a potential curative therapy. However, postsurgical recurrence rates are high with 5-year survival rate of

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“…S1 E and F). The presence of fibrotic foci is a hallmark of pancreatic cancer, and high levels of smooth muscle actin were recently correlated with poor survival of patients with advanced pancreatic ductal adenocarcinomas (17). Pdx1 was also reexpressed in both adenocarcinomas and metastases ( Fig.…”

mentioning

confidence: 99%

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann

Ward

Yew

et al. 2012

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

207

219

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Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma. P ancreatic ductal adenocarcinoma is one of the most deadly forms of cancer. In the United States, the rate of mortality is nearly equal to the rate of new diagnoses (1). Early disease detection is rare, and of those patients diagnosed with early-stage disease, only 20% are candidates for surgical resection. Approximately 50% of patients develop highly metastatic disease, for which current treatment regimens provide little increase in longevity (2). Clearly, there is a need for better biomarkers of disease and the identification of new therapeutic targets, particularly for metastatic disease.Human pancreatic cancer develops from preinvasive neoplasias, typically intraepithelial neoplasias (PanINs), although intraductal papillary mucinous neoplasia and mucinous cystic neoplasia can also give rise to adenocarcinoma (3). The majority of pancreatic adenocarcinoma is of ductal origin and contains a large desmoplastic component thought to promote tumorigenesis by modulating the tumor microenvironment. Oncogenic KRAS mutations are found in 90% of human tumors, and they appear in early PanIN (4). The accumulation of additional inactivating driver mutations in P16/CDKN2A, TP53, and SMAD4 occurs with high frequency in later-stage PanIN, and these mutations are likely required for tumor progression to invasive adenocarcinoma.Recent high-throughput sequencing efforts have shown that the majority of somatic point mutations in primary pancreatic adenocarcinoma are missense mutations and that most occur at low frequency (5). Pancreatic cancers exhibit a very unstable genome, and through whole-genome...

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α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal Adenocarcinoma

Cited by 100 publications

References 49 publications

Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients

Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

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