EDA-Fibronectin Originating from Osteoblasts Inhibits the Immune Response against Cancer

Abstract

Osteoblasts lining the inner surface of bone support hematopoietic stem cell differentiation by virtue of proximity to the bone marrow. The osteoblasts also modify their own differentiation by producing various isoforms of fibronectin (FN). Despite evidence for immune regulation by osteoblasts, there is limited knowledge of how osteoblasts modulate cells of the immune system. Here, we show that extra domain A (EDA)-FN produced by osteoblasts increases arginase production in myeloid-derived cells, and we identify α5β1 as the mediating receptor. In different mouse models of cancer, osteoblasts or EDA-FN was found to up-regulate arginase-1 expression in myeloid-derived cells, resulting in increased cancer growth. This harmful effect can be reduced by interfering with the integrin α5β1 receptor or inhibiting arginase. Conversely, in tissue injury, the expression of arginase-1 is normally beneficial as it dampens the immune response to allow wound healing. We show that EDA-FN protects against excessive fibrotic tissue formation in a liver fibrosis model. Our results establish an immune regulatory function for EDA-FN originating from the osteoblasts and identify new avenues for enhancing the immune reaction against cancer.

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

“…In a more recent study, ED-A fibronectin was shown to increase the population of myeloid derived cells, known to impair immune responses to cancer cells, from osteoblasts 21. To determine whether the absence of fibronectin impaired myeloid cell numbers and thus tumor formation, the authors subcutaneously injected melanoma cells into either a fibronectin knock out model (cKO) in which fibronectin expression in differentiating osteoblasts was conditionally deleted or a wild type animal (WT) and evaluated for tumor formation 21. Tumor growth and the presence of myeloid cells in tumors were reduced in cKO animals but not in WT animals 21.…”

“…Tumor growth and the presence of myeloid cells in tumors were reduced in cKO animals but not in WT animals 21. Although the authors don't attribute these findings to a specific reduction in the ED-A fibronectin isoform, they go on to demonstrate that culture of myeloid cells from cKO animals with ED-A fibronectin resulted in a reduction of melanoma apoptosis, suggesting that this pro-tumor effect results from ED-A activation of myeloid cells 21.…”

“…To elucidate a mechanism responsible for their observations, Ou et al found that ED-A sustains Wnt/β-catenin signaling, necessary for the progression of colorectal cancer cells, via integrin mediated activation of a FAK/ERK pathway 20. In a more recent study, ED-A fibronectin was shown to increase the population of myeloid derived cells, known to impair immune responses to cancer cells, from osteoblasts 21. To determine whether the absence of fibronectin impaired myeloid cell numbers and thus tumor formation, the authors subcutaneously injected melanoma cells into either a fibronectin knock out model (cKO) in which fibronectin expression in differentiating osteoblasts was conditionally deleted or a wild type animal (WT) and evaluated for tumor formation 21.…”

“…To determine whether the absence of fibronectin impaired myeloid cell numbers and thus tumor formation, the authors subcutaneously injected melanoma cells into either a fibronectin knock out model (cKO) in which fibronectin expression in differentiating osteoblasts was conditionally deleted or a wild type animal (WT) and evaluated for tumor formation 21. Tumor growth and the presence of myeloid cells in tumors were reduced in cKO animals but not in WT animals 21. Although the authors don't attribute these findings to a specific reduction in the ED-A fibronectin isoform, they go on to demonstrate that culture of myeloid cells from cKO animals with ED-A fibronectin resulted in a reduction of melanoma apoptosis, suggesting that this pro-tumor effect results from ED-A activation of myeloid cells 21.…”

Age-related host factors regulate lung cancer progression.

“…Our data suggest that this aberrant repair in the aged lung is facilitated by fibronectin EDA, which is not only increased in the aging lung, but also increased in the aging lung in response to bleomycin, when compared to young lungs. It is important to note that these mechanisms may vary in different cancers as aging does not appear to affect tumor progression similarly when different tumors are tested [130].…”