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Adrenomedullin is a therapeutic target in colorectal cancer

Liangjing Wang1, Manish Gala, Masayoshi Yamamoto

  • 1Gastrointestinal Unit Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Gastroenterology Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

International Journal of Cancer
|February 13, 2014
PubMed

Insights

Mutant KRAS in colorectal cancer (CRC) upregulates Adrenomedullin (ADM) under hypoxia, promoting tumor growth. Targeting ADM suppressed tumor angiogenesis and invasion, suggesting it as a novel therapeutic target in KRAS-mutated CRCs within hypoxic environments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The KRAS oncogene plays a critical role in colorectal cancer (CRC) progression, influencing angiogenesis, metastasis, and chemoresistance.
  • Hypoxic conditions within the tumor microenvironment significantly enhance these KRAS-driven processes.
  • Understanding the interplay between mutant KRAS and hypoxia is crucial for identifying effective therapeutic strategies.

Purpose of the Study:

  • To investigate the functional activities of mutant KRAS in a hypoxic microenvironment.
  • To identify genes upregulated by mutant KRAS under hypoxia.
  • To evaluate Adrenomedullin (ADM) as a potential therapeutic target in KRAS-mutated colorectal cancer.

Main Methods:

  • cDNA microarray experiments in isogenic colon cancer cell lines (DKs5 and DKO3) differing in mutant KRAS expression.
  • Gene expression analysis of Adrenomedullin (ADM) following ectopic expression or knockdown of mutant KRAS in various colon cancer cell lines (Caco-2, HCT116, DLD1, SW480).
  • Assessment of ADM's role in tumor xenografts by evaluating angiogenesis, apoptosis, and tumor suppression after ADM knockdown.
  • In vitro studies on colon cancer cell invasion and analysis of ADM expression in patient CRC samples with KRAS mutations.

Main Results:

  • Adrenomedullin (ADM) was identified as a significantly upregulated gene in cells expressing mutant KRAS under hypoxic conditions.
  • Mutant KRAS expression induced ADM, while its selective knockdown suppressed ADM expression in hypoxia.
  • ADM knockdown in colon tumor xenografts inhibited angiogenesis, promoted apoptosis, and suppressed tumor growth.
  • ADM was found to regulate colon cancer cell invasion in vitro and was significantly upregulated in CRC patients with KRAS mutations.

Conclusions:

  • Adrenomedullin (ADM) is a novel target of oncogenic KRAS specifically within the hypoxic tumor microenvironment.
  • Targeting ADM demonstrates therapeutic potential by inhibiting angiogenesis, invasion, and promoting apoptosis in KRAS-mutated colorectal cancers.
  • These findings suggest that the tumor microenvironment, particularly hypoxia, influences the choice of therapeutic targets in CRC.
Keywords:
K-rasadrenomedullincolorectal cancershypoxia

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