IFN-β Signaling Positively Regulates Tumorigenesis in Aggressive Fibromatosis, Potentially by Modulating Mesenchymal Progenitors

Abstract

Aggressive fibromatosis (also called desmoid tumor) is a benign, locally invasive, soft tissue tumor composed of cells with mesenchymal characteristics. These tumors are characterized by increased levels of B-catenin-mediated T-cell factor (TCF)-dependent transcriptional activation. We found that type 1 IFN signaling is activated in human and murine aggressive fibromatosis tumors and that the expression of associated response genes is regulated by B-catenin. When mice deficient for the type 1 IFN receptor (Ifnar1À/À) were crossed with mice predisposed to developing aggressive fibromatosis tumors (Apc/Apc1638N), a significant decrease in aggressive fibromatosis tumor formation was observed compared with littermate controls, showing a novel role for type 1 IFN signaling in promoting tumor formation. Type 1 IFN activation inhibits cell proliferation but does not alter cell apoptosis or the level of B-catenin-mediated TCF-dependent transcriptional activation in aggressive fibromatosis cell cultures. Thus, these changes cannot explain our in vivo results. Intriguingly, Ifnar1À/À mice have smaller numbers of mesenchymal progenitor cells compared with littermate controls, and treatment of aggressive fibromatosis cell cultures with IFN increases the proportion of cells that exclude Hoechst dye and sort to the side population, raising the possibility that type 1 IFN signaling regulates the number of precursor cells present that drive aggressive fibromatosis tumor formation and maintenance. This study identified a novel role for IFN type 1 signaling as a positive regulator of neoplasia and suggests that IFN treatment is a less than optimal therapy for this tumor type. [Cancer Res 2007;67(15):7124-31]

Medical treatment of mammary desmoid-type fibromatosis: which benefit?

“…Partial response has been observed in a patient with temporal fossa [34] and foot [35] fibromatosis. A study showed that IFN signaling is regulated by the β-catenin pathway [36]. IFN-α therapy did not allow tumoral response, which may be explained by experimental evidence.…”

“…According to Tjandra et al, IFN may decrease the proliferation of fibromatosis tumor cells, but do not affect tumoral stem cells, which may increase their proportion in the tumor. These stem cells are resistant to IFN, which could also explain the resistance to treatment [36]. Moreover, IFN-induced asthenia and daily subcutaneous administration may limit treatment observance.…”

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…The type I IFN receptor is ubiquitously expressed by host cells, including tumor cells. Intriguingly, a host defect related to type I IFNs or their signaling can result in different cell-type transformations and tumorigenesis (1)(2)(3)(4). In fact, type I IFNs are known to effectively activate DC maturation and are required for the early stage priming of tumor-specific T cells (5,6).…”

Mutant p53 Attenuates the Anti-Tumorigenic Activity of Fibroblasts-Secreted Interferon Beta

“…On the one hand, IFNβ directly inhibits tumor growth when secreted by the tumor microenvironment [18]. On the other hand, IFNβ partakes in tumor escape from the immune system, either by selecting for IFN non-responsive cells [19] or by contributing to oncogenic Ras transformation [20] and enriching for cancer initiating cells [21]. Although IFNβ seems to cooperate with wild type p53 in tumor suppression and stress responses [22], [23], [24], its interaction with the mutant forms of p53 has not been investigated.…”