Normal fibroblasts responding to anoxia exhibit features of the malignant phenotype.

Cancer has two fundamental features: neoplasia, representing the aberrant expression of a normal cell proliferation response, and malignancy, an ability to penetrate normal tissue boundaries. Although the role of oncogenes in neoplastic transformation is becoming clearer, malignancy remains far less well understood. Normal rat fibroblasts exhibit a staged response to anoxia which, if expressed in an uncontrolled fashion, may contribute vital aspects to the malignant phenotype. The response begins with induction of retrotransposon-like VL30 element transcription, progresses through induction of several intracellular proteins, and is followed by secretion of three major proteins including the protease cathepsin L. The induced VL30 element RNA encodes a 61-kDa secretory protein of unknown function. The response of fibroblasts to anoxia is evidently not a survival response. Instead, the response represents a close match to the role of fibroblasts during the early stages of wound healing where they are active under near-anoxic conditions. Malignant cancer cells are known to exhibit several of the characteristics we find induced in fibroblasts by anoxia. Conversion to the malignant phenotype may represent coordinate loss of control of this normal cellular response.