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
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carbonic Anhydrase IX / antagonists & inhibitors*
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Carbonic Anhydrase IX / genetics
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Carbonic Anhydrase IX / metabolism
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / pharmacology*
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Disease Progression
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Esophageal Neoplasms / drug therapy*
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Esophageal Neoplasms / metabolism
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Esophageal Neoplasms / pathology
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Female
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Humans
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Hypoxia / drug therapy*
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Hypoxia / metabolism
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Hypoxia / pathology
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Male
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Middle Aged
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Molecular Structure
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Structure-Activity Relationship
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Tissue Array Analysis
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Tumor Cells, Cultured
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Tumor Microenvironment / drug effects*
Substances
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Antigens, Neoplasm
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Antineoplastic Agents
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Carbonic Anhydrase Inhibitors
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CA9 protein, human
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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.