Review: NF-kB activation in canine cancer

Abstract

Spontaneous tumors in dogs share several environmental, epidemiologic, biologic, clinical and molecular features with a wide variety of human cancers, making this companion animal an attractive model. Nuclear factor kappa B (NF-kB) transcription factor overactivation is common in several human cancers, and there is evidence that similar signaling aberrations also occur in canine cancers including lymphoma, leukemia, hemangiosarcoma, mammary cancer, melanoma, glioma, and prostate cancer. This review provides an overview of NF-kB signaling biology, both in health and in cancer development. It also summarizes available evidence of aberrant NF-kB signaling in canine cancer, and reviews antineoplastic compounds that have been shown to inhibit NF-kB activity used in various types of canine cancers. Available data suggest that dogs may be an excellent model for human cancers that have overactivation of NF-kB.

Immunohistochemical evidence of NF-kB activation in canine lymphomas, histiocytic sarcomas, hemangiosarcomas, and mast cell tumors

“…This difference in nuclear localization is also present in a pilot immunocytochemistry experiment in DH82 HS cells that was presented in previous work. 36,37 There was not a detectable difference in pre-and post-treatment p65 nuclear labeling intensity in the other cell lines. All cell lines evaluated appeared to have strong nuclear labeling localization of p100/p52.…”

“…Some canine and human cancer literature, as reviewed previously, supports constitutive nuclear factor kappa B (NF-kB) signaling as a therapeutic target in both canine and human tumors. 37 NF-kB proteins are a family of structurally related, eukaryotic transcription factors that have more than 400 genetic targets and are involved in many vital cellular processes, including innate immunity, inflammatory responses, development, cellular growth, and survival. As a transcription factor, NF-kB is typically held as a heterodimer in an inhibited state within the cytoplasm and, following activation, moves into the nucleus to initiate transcription of downstream target genes.…”

Review: The PI3K-AKT-mTOR signal transduction pathway in canine cancer

“…14 NFκΒ mediates multiple oncogenic phenotypes, which have been described in a recent review. 232 pAKT functions to promote NFκΒ activity in 3 ways: phosphorylating and thereby activating the alpha subunit of the inhibitor of nuclear factor kappa B (IκB) kinase (IKK), which allows NFκΒ to enter the nucleus for transcription; stimulation of IKK activity via mitogen-activated protein kinase kinase kinase 8; and stimulation of NFκΒ p65 transactivation via IKK and p38/mitogen-activated protein kinase (MAPK) signaling. 119,164,220…”

“…10 In addition to inhibiting these apoptotic pathways, PI3K-AKT signal transduction also inhibits caspase-mediated apoptosis through IKK-IκB-NFκB signaling to increase expression of survival genes, including BCL2-like 1. 232…”

Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma

“…While experimental cancer models used in carefully controlled studies will continue to be essential to assess the toxicology, mechanisms, and initial antitumor activity of cancer drugs, there is a crucial need for additional complementary models that more closely represent human cancer. Pet dogs with specific forms of naturallyoccurring cancer are rapidly emerging as complementary animal models for cancer treatment research as canine cancer more closely mimics human cancer in pathological, cellular, and molecular features; cancer heterogeneity; aggressive metastatic behavior; host immunocompetence; and treatment response (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Dogs are also large enough for procedures such as those involving surgery, endoscopy, various imaging modalities, and the evaluation of medical devices.…”