Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

Hamada, Shin; Masamune, Atsushi; Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa; Hamada, Hirofumi; Kobune, Masayoshi; Satoh, Kennichi; Shimosegawa, Tooru

doi:10.1016/j.bbrc.2012.04.014

Cited by 144 publications

(99 citation statements)

References 29 publications

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“…Indirect co-culture of pancreatic cancer cell lines Panc-1 and AsPC-1 with PSCs enhanced the spheroid formation in low-adhesion coated plates, also a feature of CSCs. Along with this change, the expression of CSCrelated genes was up-regulated in pancreatic cancer cells co-cultured with PSCs [78]. The up-regulated genes included ABCG2, Nestin and LIN28.…”

Section: Cancer Stem Cell-related Phenotypes and Tumor-stromal Interamentioning

confidence: 86%

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

2013

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Chronic inflammation has a certain impact on the carcinogenesis of the digestive organs. The characteristic tissue structure of pancreatic cancer, desmoplasia, results from inflammatory processes induced by cancer cells and stromal cells. Concerning the progression of pancreatic cancer, recent research has clarified the pivotal role of tumorstromal interaction, which promotes the development of an invasive phenotype of cancer and provides survival advantages against chemotherapeutic agents or immune surveillance. Tumor stromal cells such as pancreatic stellate cells and immune cells establish a microenvironment that protects cancer cells through complex interactions. The microenvironment of pancreatic cancer acts as a niche for pancreatic cancer stem cells from which therapy-resistance and disease recurrence develop. Inhibition of the stromal functions or restoration of the immune reaction against cancer cells has therapeutic benefits that enhance the efficacy of conventional therapies. Some of the recent advances in this field are now under evaluation in clinical settings, but many problems must be overcome to establish a radical therapy for pancreatic cancer. This review summarizes current knowledge about the tumor-promoting stromal functions, immune system modulation and therapeutic strategies targeting tumorstromal interactions in pancreatic cancer.

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Section: Cancer Stem Cell-related Phenotypes and Tumor-stromal Interamentioning

confidence: 86%

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

2013

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“…In fact, many studies have shown that pancreatic stellate cells are crucial contributors to pancreatic ductal adenocarcinoma progression and are the principle source of fibrillar collagens, other extracellular matrix proteins, and soluble factors that promote the growth, invasion, metastasis, and survival of cancer cells. [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.…”

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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“…In fact, prior studies have shown decreased response to gemcitabine and radiation when cancer cells were exposed to PSCs [7]. In addition, interactions between the tumor and surrounding stromal cells have been linked with tumorigenesis, metastasis, and an increased expression of cancer stem cell-related genes [6,33]. Through IHC and ELISA experiments, we have shown that chemokine CCL25 is expressed by both PANC-1 pancreatic cancer cells and PSCs.…”

Section: Discussionmentioning

confidence: 78%

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

Heinrich

Arrington

et al. 2013

Cancer Microenvironment

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Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC-and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.

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Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

Cited by 144 publications

References 29 publications

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

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

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

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