Substance P-Fibronectin-Cytokine Interactions in Myeloproliferative Disorders with Bone Marrow Fibrosis

Abstract

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-β, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.

Bone Marrow Stroma Influences Transforming Growth Factor-β Production in Breast Cancer Cells to Regulate c-myc Activation of the Preprotachykinin-I Gene in Breast Cancer Cells

“…The PPT-I gene, linked to the endocrine system, has been associated with the biology of both BC and the BM (13,14). PPT-I is a single copy, 7-exon gene that produces peptides that are conserved by evolution (15).…”

Biology of breast cancer bone metastasis

“…In normal bone marrow stroma, NK-1 and NK-2 regulate the expression of each other and have opposing functions. 76 There is evidence that coexpression of NK-1 and NK-2 in breast cancer cells is stimulated by PPT-I through autocrine mechanisms; NK-1 and NK-2 mediate homing of breast cancer cells in the bone microenvironment; and their effects can be blunted by using NK-1 and NK-2 antagonists. 77,78 …”

Connective tissue growth factor expression in endocrine tumors is associated with high stromal expression of α-smooth muscle actin

“…The mechanism behind carcinoid-associated fibrosis is not established; yet, the list of factors that have been implicated is long. Carcinoid-produced hormones, serotonin (2) and tachykinins (3)(4)(5), have been shown to be related to fibroblast growth and fibrotic changes in the heart valves. Growth factors produced in ileal carcinoids such as platelet-derived growth factor, insulin-like growth factors 1 and 2 (IGF1 and 2), epidermal growth factor (EGF), and transforming growth factors a and b (TGFA and TGFB) and their receptors have also been postulated as potential mediators in the context of carcinoid fibrosis (6)(7)(8)(9).…”