Systemic transforming growth factor‐beta in patients with bone marrow fibrosis—pathophysiological implications

Rameshwar, Pranela; Chang, Victor Tsu-Shih; Thacker, Usha F.; Gascón, Pedro

doi:10.1002/(sici)1096-8652(199810)59:2<133::aid-ajh6>3.3.co;2-y

Cited by 14 publications

(16 citation statements)

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“…Detection of high levels of circulating TGF-β1 in HCL patients is an important finding and is in agreement with the recent data of Rameshwar et al, who demonstrated that systemic TGF-β1 is elevated in patients with idiopathic and secondary myelofibrosis (50). TGF-β is usually produced as a large latent complex, and the active form has to be released to produce biological effects (51).…”

Section: Discussionsupporting

confidence: 88%

TGF-β1 induces bone marrow reticulin fibrosis in hairy cell leukemia

Shehata¹,

Schwarzmeier²,

Hilgarth³

et al. 2004

J. Clin. Invest.

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Nonstandard abbreviations used: B cell chronic lymphocytic leukemia (B-CLL); bone marrow (BM); BM fibroblast (BMF); BM mononuclear cell (BMMC); BM plasma (BMP); BM stromal cell (BMSC); hairy cell (HC); HC leukemia (HCL); healthy donor (HD); peripheral blood plasma (PBP); procollagen type III aminoterminal propeptide (PIIINP). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionHairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by the presence of hairy cells (HCs) in peripheral blood, bone marrow (BM), and spleen and is invariably associated with a unique type of BM fibrosis (1-3). Although a rare disease (2% of adult leukemia), HCL represents an excellent model for cancer biotherapy (4) and for understanding the deregulation of cytokines and growth factors in human neoplasia (5-7). The fibrotic process and the associated structural abnormality in BM of HCL patients are mainly due to accumulation of fine argyrophilic reticulin fibers, although collagen fibers can be observed in the advanced stages of the disease (8-11). The composition of reticulin fibers in HCL is not well defined. In normal and fibrotic BM, the distribution of reticulin fibers is identical to that of type III collagen and its precursor, type III procollagen (12,13). Electron microscopic studies of human tissues revealed that reticulin fibers are individual collagen fibrils or small bundles of these fibrils embedded in the interfibrillar matrix of proteoglycans (14-16) and that they are composed mainly of type III collagen surrounding a core of type I collagen fibrils (17,18). In addition to reticulin fibrosis, it has been recently demonstrated that the glycoprotein fibronectin, which is produced and assembled by HCs, contributes to the fibrotic process in BM of HCL patients (19). This process was also found to be particularly enhanced by bFGF, which is endogenously produced by the HCs (20). Since reticulin and fibronectin fibers were found to represent different structures in myelofibrotic BM (21), it appears that BM fibrosis in HCL is a complex process that involves accumulation and assembly of collagenous ECM components (reticulin) (22) and noncollagenous ECM components (fibronectin).In BM, HCs are found in association with randomly dispersed fibroblastoid cells and are surrounded by reticulin fibers (9, 10, 23, 24). These fibroblastoid cells, which have been found in close association with collagen fibers, are the matrix-producing cells and are responsible for the synthesis of reticulin and collagen (9,(25)(26)(27)(28). Other studies confirmed the increase in the collagen fibrils in the intercellular space around the HCs but did not find evidence that HCs give rise to these fibrils (10). These studies also showed that HCs are not argyrophilic (29), suggesting that they may not be the direct source of reticulin fibers. Since no massive increase in fibroblast numbers is observed in the BM of HCL patients (10), the increased production of reticulin and ECM proteins mig...

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Section: Discussionsupporting

confidence: 88%

TGF-β1 induces bone marrow reticulin fibrosis in hairy cell leukemia

Shehata¹,

Schwarzmeier²,

Hilgarth³

et al. 2004

J. Clin. Invest.

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“…85,86 The NF-B pathway has been shown to be activated and implicated in the abnormal release of TGF-␤ in PMF, implying an important role of NF-B activation in the development of bone marrow fibrosis. [87][88][89] As noted previously, TGF-␤ is highly immunosuppressive, impairing the functionality of several immune cells (dendritic cells, NK cells, and cytotoxic T cells) involved in tumor immune surveillance. 61,63 Accordingly, by enhancing TGF-␤ release in the bone marrow, NF-B activation may not only promote fibrosis but also indirectly promote expansion of the malignant clone by suppressing immune cells.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?

Hasselbalch

2012

Blood

279

301

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The morbidity and mortality of patients with the chronic Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis are mainly caused by cardiovascular diseases, thrombohemorrhagic complications, and bone marrow failure because of myelofibrosis and leukemic transformation. In the general population, chronic inflammation is considered of major importance for the development of atherosclerosis and cancer. MPNs are characterized by a state of chronic inflammation, which is proposed to be the common denominator for the development of "premature atherosclerosis," clonal evolution, and second cancer in patients with MPNs. Chronic inflammation may both initiate clonal evolution and catalyze its expansion from early disease stage to the myelofibrotic burnt-out phase. Furthermore, chronic inflammation may also add to the severity of cardiovascular disease burden by accelerating the development of atherosclerosis, which is well described and recognized in other chronic inflammatory diseases. A link between chronic inflammation, atherosclerosis, and second cancer in MPNs favors early intervention at the time of diagnosis (statins and interferon-␣2), the aims being to dampen chronic inflammation and clonal evolution and thereby also diminish concurrent diseasemediated chronic inflammation and its consequences (accelerated atherosclerosis and second cancer).

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“…This is because the mechanisms for myelofibrosis are poorly understood [170][171][172] and the means for quantitating it imprecise due to the patchy nature of the process. 168,[173][174][175] Furthermore, with respect to diagnosis, it has generally been assumed that polycythemia vera and idiopathic myelofibrosis are closely related disorders, 152 although apart from phenotypic similarities, this assumption has never been substantiated scientifically.…”

Section: Myelofibrosismentioning

confidence: 99%