Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1

Abstract

As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from CML and AML patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (RT-PCR) and protein level (FACS) and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 MAPK and AKT. We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (e.g., as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK–HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating expansion of leukemia/lymphoma cells when the ComC becomes activated.

Complement in cancer: untangling an intricate relationship

“…C3 expression is then correlated with increased cell invasiveness through downregulation of E-cadherin on the surface of cancer cells and promotion of EMT 94 . In addition, leukaemia cell lines as well as clonogenic blasts derived from patients with chronic myeloid leukaemia or acute myeloid leukaemia show increased cell adhesion in response to C3a and C5a fragments 95 . In a model of gastric cancer, C5a promoted the invasiveness of human gastric cancer cell lines (the adenosquamous carcinoma cell line MKN1 and the tubular adenocarcinoma cell line MKN7) via conversion of RhoA-guanosine diphosphate (RhoA-GDP) to RhoA-guanosine triphosphate (RhoA-GTP), resulting in morphological cell changes and increased expression of stress fibres and filopodia 92 .…”

HO-1 inhibits migration of leukemic cells

“…The complement cascade (ComC) is a crucial element of innate immunity and is involved in several processes related to fighting infection by releasing active mediators, including C3a and desArgC3a, which result from cleavage of complement component 3 (C3), and C5a and desArgC5a, which result from cleavage of complement component 5 (C5) [ 1 - 3 ]. In parallel, evidence has accumulated that, in addition to their immunological functions, ComC cleavage fragments modulate stem cell migration during organogenesis [ 2 ].…”

“…For example, although HSPCs express the functional C5a receptor (C5aR, also known as CD88), and respond to stimulation by C3a, surprisingly these cells do not show spontaneous chemotaxis in response to C3a, C5a, desArgC3a, or desArgC5a [ 3 ]. In contrast, all these C3 and C5 cleavage fragments promote migration of already differentiated hematopoietic cells, including granulocytes, monocytes, lymphocytes, and NK cells [ 1 - 3 ].…”

“…Nevertheless, in contrast to solid tumors, the potential involvement of the ComC in leukemia has not been studied extensively. To fill in this knowledge gap, we asked whether human leukemia cell lines and primary patient leukemic blasts express functional C3 and C5 cleavage-fragment receptors (C3aR and C5aR, respectively) and whether activation of the ComC and release of C3a and C5a anaphylatoxins affects the biology of leukemic cells [ 1 ]. This question was prompted by our hypothesis that infections accompanying leukemia and/or the application of chemotherapy in leukemic patients trigger activation of the ComC and the release of potent mediators derived from C3 and C5 cleavage.…”

“…This question was prompted by our hypothesis that infections accompanying leukemia and/or the application of chemotherapy in leukemic patients trigger activation of the ComC and the release of potent mediators derived from C3 and C5 cleavage. In our experiments we employed several established human myeloid and lymphoma cell lines, purified CD33 + blasts from leukemia patients, and studied the effect of C3a, C5a, desArgC3a, and desArgC5a on the proliferation, survival, migration, and adhesion of these cells [ 1 ].…”