Abstract
The effective prevention of tumor initiation, especially for potentially inoperable tumors, will be beneficial to obtain an overall higher quality of our health and life. Hence, thorough understanding of the pathophysiological mechanisms of early tumor formation arising from identifiable cellular origins is required to develop efficient preventative and early treatment options for each tumor type. Here, using genetically engineered mouse models, we provide preclinical experimental evidence for a long-standing open question regarding the pathophysiological potential of a microenvironmental and physiological stressor in tumor development, gastric acid-mediated regional microscopic injury in foregut squamous epithelia. This study demonstrates the association of gastric acid stress with Cyclooxygenase-2-dependent tumor formation originating from tumor-competent Krt5+/Krt15+ foregut basal progenitor cells. Our findings suggest that clinical management of microenvironmental stressor-mediated microscopic injury may be important in delaying tumor initiation from foregut basal progenitor cells expressing pre-existing tumorigenic mutation(s) and genetic alteration(s).
Highlights
The effective prevention of tumor initiation, especially for potentially inoperable tumors, will be beneficial to obtain an overall higher quality of our health and life
This study further reveals that gastric acid stressinduced acceleration of tumor formation from mutant foregut basal progenitors is dependent on epithelial-specific prostaglandin-endoperoxide synthase 2 (Ptgs[2], known as cyclooxygenase-2, Cox-2) expression
Squamous papillomas are considered a precursor lesion that have the potential to evolve into a squamous cell carcinoma, which were observed throughout the entire forestomach tissue (Fig. 1a–c)
Summary
The effective prevention of tumor initiation, especially for potentially inoperable tumors, will be beneficial to obtain an overall higher quality of our health and life. It is important to note that stem cell division rate appears to play a crucial role in the development of driver mutations for tumors, cellular extrinsic stressors can often prove to be the tipping point for whether or not genetically prone cells become tumorigenic[4,5] In addition to these mathematical hypotheses, several lines of experimental evidence support the hypotheses that preventing stress factors could potentially reduce the lifetime risk of cancer[6,7,8]. Using genetically engineered mouse models, we investigated if microenvironmental gastric acid stress can act as a co-promoting factor, which may significantly accelerate early tumor formation from foregut squamous epithelia, from mutant long-lived basal progenitor cells expressing a preexisting oncogenic load. This study demonstrates the significant contribution of physiological acid stress as a co-promoting factor in foregut tumor initiation from tumor-competent Krt5+/Krt15+ basal progenitor cells
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