The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma

Erkan, Mert; Michalski, Christoph; Rieder, Simon; Reiser–Erkan, Carolin; Abiatari, Ivane; Kolb, Armin; Giese, Nathalia A.; Espósito, Irene; Frieß, Helmut; Kleeff, Jörg

doi:10.1016/j.cgh.2008.05.006

Cited by 378 publications

(332 citation statements)

References 31 publications

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“…These unique characteristics limit drug delivery and facilitate the rapid emergence of resistant clones. 13,14 Therefore, we sought to develop a novel and effective T cell-based therapy that would overcome these challenges. The clinical benefits of this approach have been validated using CAR-CD19 T cells to treat a range of CD19 + hematological malignancies including B cell chronic lymphocytic leukemia (B-CLL) and acute lymphoblastic leukemia (ALL).…”

Section: Discussionmentioning

confidence: 99%

“…As a therapeutic alternative, we developed a PSCA-directed CAR and demonstrated that transgenic cells were able to efficiently and selectively eliminate antigen-expressing tumors in both in vitro and in vivo xenograft mouse models. 12 However, malignant cells comprise only 10%-40% of the tumor, 13,14 while the rest is a complex desmoplastic matrix consisting of extracellular proteins, stellate cells, and immunomodulatory cells that produce cytokines including interleukin-4 (IL-4), IL-10, and transforming growth factor b (TGF-b) that promote fibrogenesis, support tumor growth and protect malignant cells from immune destruction. [15][16][17][18][19][20] Thus, in order to provide clinical benefit to patients with PDAC, it is likely that the tumor-targeting T cells will require additional engineering to enable them to withstand this hostile environment.…”

Section: Introductionmentioning

confidence: 99%

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Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Sukumaran²,

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Sukumaran²,

et al. 2017

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“…There is emerging interest to stratify patients on the basis on stromal characteristics. 61,62 Stromal collagen topology has already been shown to correlate with breast tumors that have a greater propensity to metastasize and negatively impact prognosis. 16 It is likely that a diversity of collagen topology profiles exist in pancreatic ductal adenocarcinoma tumors, which may prove useful as an ancillary disease marker to subtype patients during histological evaluation.…”

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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“…Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises prognosis in some animal models and early-stage clinical trials (11,32,42). α-smooth muscle actin (αSMA) secreted by CAF is confirmed as a negative prognostic factor in PDA (44).…”

Section: Review Articlementioning

confidence: 99%

“…The prominent feature of PDA is dense desmoplastic stroma, sometimes comprising up to 80% of tumor mass (42). As early as a decade ago, researchers found that highly heterogeneous components of the stroma, consisting of immune cells, CAF, ECM as well as varieties of proteins, enzymes, growth factors and cytokines, form a sophisticated network interacted with tumor cells (43).…”

Section: The Biology Of Stromal Cells In Pdamentioning

confidence: 99%

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

Mei¹,

Du²,

Wee³

2016

J. Gastrointest. Oncol.

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Pancreatic cancer is a highly lethal disease. Conventional therapeutics targeting pancreas cancer cell compartment using cytotoxics improved patient survival but at the expense of significant toxicity.Microscopically, the tumor is characterized by thick desmoplastic stroma that surrounds islands of pancreatic cancer cells. The tumor microenvironment has been found to play important roles in carcinogenesis, the development of drug resistance, and mediating immunosuppression. The understanding the tumor-stromal interaction has led to the development of novel therapeutic approaches. Here, we review the strategies that are currently in (or, near to) clinical evaluation and the underlying preclinical rationales.

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The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma

Cited by 378 publications

References 31 publications

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

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

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

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