Stromal abnormalities in neoplastic bone marrow diseases

Abstract

Bone marrow malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem or progenitor cells. Similar to their normal counterparts, transformed blood-forming cells remain dependent on signals from the hematopoiesis-regulating stromal environment for survival and proliferation. There is increasing evidence that the microenvironment may also take a more active part in the disease process. A review of the literature on stromal abnormalities in the leukemias, the myelodysplastic syndromes, and multiple myeloma reveals three principal mechanisms by which stromal derangements can contribute to the evolution of a neoplastic disease. In the simplest case, neoplastic blood-forming cells induce reversible changes in stroma function or composition which result in improved growth conditions for the malignant cells ('malignancy-induced microenvironment'). In the second setting, functionally abnormal end cells derived from the malignant clone become an integral part of the stroma system, selectively stimulating the neoplastic cells and inhibiting normal blood cell formation ('malignant microenvironment'). In the third condition, the emergence of a neoplastic cell population is the consequence of a primary stroma lesion characterized by inability to control regular blood cell formation ('malignancy-inducing microenvironment'). The perception of different stroma-related disease mechanisms may eventually lead to the development of alternative therapeutic approaches.

In vitro effects of native human acute myelogenous leukemia blasts on fibroblasts and osteoblasts

“…39,40 Previous studies have described reduced numbers of colony-forming fibroblasts in AML bone marrow, 6 and our present results support this conclusion and suggest that the number of other important stromal cells may also be reduced in AML. Although the local levels of certain AML-derived cytokines are increased during coculture, the molecular mechanisms behind the AML-induced antiproliferative effect on nonleukemic cells are probably heterogeneous and not caused by a single mediator.…”

“…[3][4][5][6][7][8][9][10][11][12][13][15][16][17] The molecular bidirectional crosstalk with stromal cells appears to support AML blast proliferation, [3][4][5][6][7][8][9]16,20,22 and our own prior studies demonstrated that both fibroblast cell lines HFL1 and Hs27, the osteoblastic sarcoma cell lines Cal72 and SJSA-1 and normal osteoblasts 33,34 can increase AML blast proliferation as well as release of proangiogenic IL-8 by native human AML cells. Fibroblasts also have an additional antiapoptotic effect, 22 and this effect is observed both with Hs27 and HFL1 fibroblasts (Ryningen, unpublished).…”

“…[1][2][3][4][5][6][7][8][9] Firstly, normal myeloid cells as well as AML blasts express adhesion molecules that bind to stromal elements. These molecules include ␤1 (CD29) and ␤2 (CD18) integrins, the immunoglobulins PECAM-1 (CD31) and LFA-3 (CD58), L-selectin and the proteoglycan CD44.…”

Transplantation of stromal cells transduced with the human IL3 gene to stimulate hematopoiesis in human fetal bone grafts in non-obese, diabetic-severe combined immunodeficiency mice

“…In malignant diseases, stromal dysfunctions can result from modifications of adhesion molecule expression or growth factor production by stromal cells. 1 Recent data indicate that infection of bone marrow stromal cells by human immunodeficiency virus in vitro lessens their ability to support hematopoiesis. 2,3 Stromal cells are now proposed as targets for gene therapy of some hematological disorders.…”

Biological Response Modifiers Influence Structure Function Relationship of Hematopoietic Stem and Stromal Cells in a Mouse Model of Leukemia

“…Leukemia development is a multistep process characterized by progressive cellular transformation of normal hematopoietic stem/progenitor cells into malignant leukemic clones. The functionally abnormal malignant clones become an integral part of the stromal system, selectively stimulating neoplastic cells and inhibiting normal blood cell formation (malignant microenvironment) (Duhrsen & Hossfeld, 1996). Although malignant cells have an intrinsic growth and survival advantage, but they also remain dependent on some factors provided by the malignant microenvironment.…”