Cochineal extracts (CE) is a coccid-derived natural food colorant containing
carminic acid (CA) as an active ingredient that potentiates inhibition of tissue proteolysis mediated by activation of plasma
hyaluronan-binding protein (PHBP). In our previous study, dietary administered CE (CA: 28.5% in CE) has shown to promote the macroscopic development of capsular invasive
carcinomas (CICs) associated with up-regulation of angiogenesis-related genes in an intracapsular invasion model of experimental
thyroid cancers using rats. However, the promoting effect of CE could not be confirmed histopathologically. The purpose of the present study was to confirm the promoting effect of CE through direct
injections to animals on the development of CICs using this
cancer invasion model. One week after initiation with N-bis(hydroxypropyl)
nitrosamine, male F344/NSlc rats were administered CA-enriched CE (CA: 52.6% in CE) by
intraperitoneal injections every other day (10 mg/kg
body weight) during the promotion with 0.15%
sulfadimethoxine in the
drinking water for 8 weeks. The multiplicities of macroscopical CICs and the mean area of early capsular invasive foci estimated by
Tenascin (TN)-C-immunoreactivity in the thyroid significantly increased with CE-treatment, while the number of TN-C-positive foci did not change with CE. Transcript level of Phbp and downstream genes unchanged; however, transcript level of angiogenesis-related genes, i.e, Vegfb and its
transcription factor gene, Hif1a, those being downstream of
phosphatase and
tensin homolog (PTEN)/Akt signaling, up-regulated in the thyroid tissue with CE-administration. These results suggest that CE potentiates promotion activity by facilitating angiogenesis through activation of PTEN/Akt signaling without accompanying modification of PHBP-related proteolysis.