Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer
Kuan-Te Fang1, Hsin Hung1, Nga Yin Sadonna Lau1,2
1Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
Abstract:
The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK-an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.
Insights
Deleting LKB1 and PTEN genes in stomach cells promotes gastric cancer (G.C.) development. This creates a tumor microenvironment supporting G.C. cell proliferation, angiogenesis, and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- LKB1 and PTEN are crucial tumor suppressor genes involved in gastric cancer (G.C.) development.
- LKB1 regulates cellular metabolism and epithelial junction stability via AMPK and E-cadherin.
- PTEN negatively regulates the PI3K signaling pathway, a common mutation target in cancers.
Purpose of the Study:
- To investigate the role of LKB1 and PTEN in gastric cancer development using a targeted genetic approach.
- To elucidate how the loss of LKB1 and PTEN function in stomach cells contributes to G.C. tumorigenesis.
- To analyze the impact of these genetic alterations on tumor histopathology, invasiveness, metastasis, angiogenesis, and the tumor microenvironment.
Main Methods:
- Utilized the H+/K+ ATPase Cre transgene strain for cell-specific Cre recombinase expression in stomach parietal cells.
- Achieved conditional deletion of LKB1 and PTEN genes specifically within the stomach.
- Monitored the development of G.C. and analyzed tumor characteristics, including histopathology, angiogenesis, and microenvironment changes.
Main Results:
- Conditional deletion of PTEN and LKB1 in the stomach successfully induced G.C. development.
- The loss of these tumor suppressors created a pro-tumorigenic microenvironment.
- This environment was characterized by increased cancer cell proliferation, enhanced angiogenesis, and promoted metastasis.
Conclusions:
- Simultaneous loss of LKB1 and PTEN function is sufficient to drive gastric cancer initiation and progression.
- The resulting tumor microenvironment significantly supports G.C. tumorigenesis through proliferation, angiogenesis, and metastasis.
- Targeted deletion of these genes provides a valuable model for studying human gastric adenocarcinoma.
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