CAIX furthers tumour progression in the hypoxic tumour microenvironment of esophageal carcinoma and is a possible therapeutic target

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1024-1033. doi: 10.1080/14756366.2018.1475369.

Abstract

The hypoxic tumour microenvironment of solid tumours represents an important starting point for modulating progression and metastatic spread. Carbonic anhydrase IX (CAIX) is a known HIF-1α-dependent key player in maintaining cell pH conditions under hypoxia. We show that CAIX is strongly expressed in esophageal carcinoma tissues. We hypothesize that a moderate CAIX expression facilitates metastases and thereby worsens prognosis. Selective inhibition of CAIX by specific CAIX inhibitors and a CAIX knockdown effectively inhibit proliferation and migration in vitro. In the orthotopic esophageal carcinoma model, the humanized HER2 antibody trastuzumab down-regulates CAIX, possibly through CAIX's linkage with HER2 in the hypoxic microenvironment. Our results show CAIX to be an essential part of the tumour microenvironment and a possible master regulator of tumour progression. This makes CAIX a highly effective and feasible therapeutic target for selective cancer treatment.

Keywords: Esophageal carcinoma; carbonic anhydrase IX; hypoxia; targeted therapy; tumour microenvironment.

MeSH terms

  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carbonic Anhydrase IX / antagonists & inhibitors*
  • Carbonic Anhydrase IX / genetics
  • Carbonic Anhydrase IX / metabolism
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Female
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Male
  • Middle Aged
  • Molecular Structure
  • Structure-Activity Relationship
  • Tissue Array Analysis
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • CA9 protein, human
  • Carbonic Anhydrase IX

Grants and funding

The work has in part been supported by grant [GR 3484/1–1] of the Deutsche Forschungsgemeinschaft (DFG) and the Hamburger Krebsgesellschaft e.V.