Abstract
Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5−CD44+ cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.
Highlights
Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems
We provide several lines of evidence supporting the critical role of osteopontin (OPN)-CD44 signaling in the initiation and progression of gastric squamous-columnar junction (SCJ) cancers
The antrum contains the majority of Lgr5+ stem cells targeted for our mutations (Supplementary Fig. 3), yet cancer incidence was strikingly higher in the SCJ (Fig. 1c)
Summary
Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. Mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. The incidence of cancers arising from the gastric squamous-columnar junction (SCJ, aka gastroesophageal junction), the area of a direct transition from the esophageal stratified squamous epithelium to the gastric glandular epithelium, has steadily increased[5,6]. Previous studies have shown that such niches may be prone to the malignant transformation Such examples include TZ in the mouse ovarian hilum region[9,14] and human tubal-peritoneal junction[15]. The mechanisms responsible for preferential susceptibility to cancer by TZ stem cells, as opposed to those in other regions of the same organ, remain insufficiently understood
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