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Yana Zavros, PhD
Assistant Professor
Co-Director, PhD Program in Systems Biology & Physiology

yana.zavros@uc.edu

Correa described the multi-step model for gastric cancer over 30 years ago beginning with an active chronic inflammatory phase now known to be typically caused by Helicobacter pylori infection. The subsequent phases are dominated by alterations of the epithelial cell cycle, progressing to atrophy, intestinal metaplasia, dysplasia and the eventual development of gastric cancer. During the progression of the inflamed stomach to gastric cancer, the acid-producing parietal cells fail to secrete acid and are replaced by metaplastic mucus-secreting cells, a process called atrophy. My past research interests have revolved around understanding the Correa model with a particular focus on the role of inflammation as a trigger for parietal-cell atrophy. To investigate the role of inflammation as a trigger for atrophy, the gastrin-deficient (G/) mouse model (developed by Linda C. Samuelson, University of Michigan) was used. Interestingly, we found that in the hypochlorhydric G/ mouse stomach the chronic gastritis, atrophy, metaplasia, dysplasia paradigm typically observed in the human was recapitulated in these mice. Therefore, the G/ mouse became an excellent model for us to study the development of gastric cancer from chronic atrophic gastritis.

Parietal cells within the stomach not only secrete acid, but are also the major source of factors that are responsible for regulating the differentiation of the gastric epithelium. Thus, it is not surprising that loss of the parietal cells triggers a cascade that develops into neoplasia. Amongst the proteins synthesized and secreted from the parietal cells is the morphogen sonic hedgehog (Shh). Remarkably, Shh is involved not only in the development of the gastrointestinal tract, but also sustains the gastric phenotype of the adult stomach. However, little is known of the interaction between Shh expression, parietal cell function and the development of gastric cancer. Gastrin, a known trophic factor for the gastric epithelium, is the principal stimulant of acid production and sustains the differentiated state of the parietal cell. We have shown that G/ mice develop parietal cell atrophy that eventually results in gastric cancer [Zavros et al, 2005].

Since loss of Shh induces a metaplastic phenotype reminiscent of the atrophy that emerges with chronic inflammation, we tested the hypothesis that gastrin regulates Shh. Indeed we found that G/ mice had reduced levels of gastric Shh expression while gastrin infusion induced Shh expression at both the mRNA and protein level. Since most Shh is in an inactive precursor form, our observation that gastrin increased the conversion of the 45-kDa Shh precursor to the 19-kDa biologically active and secreted protein was highly significant. Furthermore, the activation was associated with increased conversion of pepsinogen A (PgA) to pepsin A [Fig 1].

There is compelling evidence that gastric atrophy initiates the development of gastric cancer. Shh, produced by the parietal cell, is believed to be a key regulator of gastric differentiation. Therefore, our focus is to study the molecular mechanisms underlying the relationship between Shh processing, inflammation, parietal cell function and cancer development. Moreover, our research will extend the knowledge of the role of pepsinogen A in the stomach. Pepsin A protease function is highly significant, given that protease activity is absent in the stomachs of patients with gastric cancer that coincides with loss of Shh protein processing and bioactivity.



Selected Publications:
  • Yana Zavros, Melissa A Orr, Chang Xiao and Danuta H Malinowska (2008) Sonic hedgehog is associated with H+-K+-ATPase-containing membranes in gastric parietal cells and secreted with histamine stimulation. Am J Physiol Gastrointest Liver Physiol 295, G99-G111.
    View original publication at AJP:GI Online.
  • Yana Zavros (2008) The adventures of sonic hedgehog in development and repair. IV. Sonic hedgehog processing, secretion, and function in the stomach. Am J Physiol Gastrointest Liver Physiol 294, G1105-G1108.
    View original publication at AJP:GI Online.
  • Yana Zavros, Meghna Waghray, Arthur Tessier, Longchuan Bai, Andrea Todisco, Deborah L Gumucio, Linda C Samuelson, Andrzej Dlugosz and Juanita L Merchant (2007) Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation. J Biol Chem 282, 33265-33274.
    View original publication at JBC.org.
  • Yana Zavros, Kathryn A Eaton, Weiqun Kang, Sivaprakash Rathinavelu, Vinay Katukuri, John Y Kao, Linda C Samuelson and Juanita L Merchant (2005) Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene 24, 23542366.
    View original publication at Nature Publishing Group.
  • Yana Zavros, John Y Kao and Juanita L Merchant (2004) Inflammation and cancer III. Somatostatin and the innate immune system. Am J Physiol Gastrointest Liver Physiol 286 G698-G701. Review
    View original publication at AJP:GI Online.
  • Yana Zavros, Gabriele Rieder, Amy Ferguson, Linda C Samuelson, and Juanita L Merchant (2002) Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology 122, 119-133.
    View original publication at Elsevier.com.

Publications, Complete List at PubMed



Fig 1: Shh processing by gastrin-activated pepsinogen A (PgA)
Gastrin induces activation of PgA to pepsin A. Pepsin A cleaves Shh 45-kDa precursor to the 26-kDa and 19-kDa biologically-active secreted proteins. Secreted Shh may then regulate parietal-cell function via its receptor patched (Ptc).


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