Faculty Opinions recommendation of In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

ABSTRACTPancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.

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Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-04-1813 ◽

2005 ◽

Vol 11 (9) ◽

pp. 3587-3596 ◽

Cited By ~ 92

Author(s):

Davendra Segara ◽

Andrew V. Biankin ◽

James G. Kench ◽

Catherine C. Langusch ◽

Amanda C. Dawson ◽

...

Keyword(s):

Pancreatic Cancer ◽

Retinoic Acid ◽

Intraepithelial Neoplasia ◽

Retinoic Acid Signaling ◽

Pancreatic Intraepithelial Neoplasia

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A Case of Pancreatic Intraepithelial Neoplasia That Was Difficult to Diagnose Preoperatively

Case Reports in Oncology ◽

10.1159/000371842 ◽

2015 ◽

Vol 8 (1) ◽

pp. 30-36 ◽

Cited By ~ 5

Author(s):

Hiroyuki Ito ◽

Yoshiaki Kawaguchi ◽

Yohei Kawashima ◽

Atsuko Maruno ◽

Masami Ogawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Duct ◽

Main Pancreatic Duct ◽

Cystic Lesion ◽

Precancerous Lesion ◽

Intraepithelial Neoplasia ◽

The Body ◽

Pancreatic Ductal Carcinoma ◽

Pancreatic Intraepithelial Neoplasia ◽

Multiple Imaging

A 63-year-old female patient presented to a local physician with pain in her back and epigastric region. An abdominal computed tomography (CT) scan revealed a pancreatic tumor, and the patient was referred to our hospital. Multiple imaging studies that included ultrasonography (US), CT, MRI, and endoscopic US revealed a cystic lesion 3-4 cm in size with node-like projections in the body of the pancreas. The distal main pancreatic duct was also found to be dilated. Endoscopic retrograde pancreatography revealed an irregular stenosis of the main pancreatic duct proximal to the cystic lesion, and malignancy was suspected. The patient was preoperatively diagnosed with pancreatic ductal carcinoma concomitant with intraductal papillary mucinous carcinoma, and a distal pancreatectomy was performed. Rapid pathological diagnosis during surgery revealed positive surgical margins for pancreatic intraepithelial neoplasia (PanIN). Further resection was performed twice, her surgical margin was positive and total pancreatectomy was ultimately conducted. Histopathological findings revealed diffuse microinvasive cancerous lesions corresponding to PanIN-2 (moderate dysplasia) to PanIN-3 (carcinoma in situ) throughout the pancreas. PanIN involves microlesions of the ductal epithelium that may precede pancreatic cancer. Ascertaining changes in PanIN using images provided by diagnostic modalities such as CT and US is challenging. Ductal stenosis and distal cystic lesions resulting from atrophy and fibrosis of pancreatic tissue were noted around PanIN. Considering the possibility of PanIN, a precancerous lesion during differential diagnosis will help to improve early detection and prognosis for patients with pancreatic cancer.

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In vivo Diagnosis of Epidermal Growth Factor Receptor Expression using Molecular Imaging with a Cocktail of Optically Labeled Monoclonal Antibodies

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-1119 ◽

2007 ◽

Vol 13 (22) ◽

pp. 6639-6648 ◽

Cited By ~ 85

Author(s):

Tristan Barrett ◽

Yoshinori Koyama ◽

Yukihiro Hama ◽

Gregory Ravizzini ◽

In Soo Shin ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Monoclonal Antibodies ◽

Molecular Imaging ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Receptor Expression ◽

Epidermal Growth ◽

In Vivo Diagnosis

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Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

Stem Cells International ◽

10.1155/2016/9298535 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Maximilian Reichert ◽

Karin Blume ◽

Alexander Kleger ◽

Daniel Hartmann ◽

Guido von Figura

Keyword(s):

Pancreatic Cancer ◽

Poor Prognosis ◽

Intraepithelial Neoplasia ◽

Developmental Pathways ◽

Ductal Adenocarcinoma ◽

Pancreatic Intraepithelial Neoplasia ◽

Cellular Origin ◽

Mucinous Neoplasm ◽

Cancer Initiation ◽

Advanced Stages

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN), and intraductal papillary mucinous neoplasm (IPMN) is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized.

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