Growth differentiation factor 15 contributes to cancer-associated fibroblasts-mediated chemo-protection of AML cells

Abstract

BackgroundChemo-resistance is still a major obstacle in efforts to overcome acute myeloid leukemia (AML). An emerging concept has proposed that interactions between the bone marrow (BM) microenvironment and leukemia cells reduce the sensitivity of the leukemia cells to chemotherapy. As an important element of the tumor microenvironment, the cancer-associated fibroblasts (CAFs) are considered to be activated modulators in the chemo-resistance of many solid tumors. But their contribution to AML has yet to be fully understood. Here we report a critical role for CAFs which were thought to be a survival and chemo-protective factor for leukemia cells.MethodsA retrospective study on the BM biopsies from 63 primary AML patients and 59 normal controls was applied to quantitative analysis the fiber stroma in the BM sections. Then immunohistochemistry on the BM biopsies were used to detect the makers of the CAFs. Their effects on drug resistance of leukemia cells were further to be assessed by co-cultured experiments in vitro. Moreover, the possible mechanisms involved in CAF-mediated chemo-protection of AML cells was investigated by antibody neutralization and siRNA knockdown experiments, with particular emphasis on the role of GDF15.ResultsIn our study, excessive reticular fibers in the BM led to higher frequency of relapse and mortality in primary AML patients, bringing the inspiration for us to investigate the functional roles of the fiber-devied cells. We declared that the CAF cells which expressed higher levels of FSP1, α-SMA or FAP protein were widely distributed in the marrow of AML. Then in vitro co-cultured tests showed that these CAFs could protect leukemia cell lines (THP-1/K562) from chemotherapy. Interestingly, this effect could be decreased by either treatment with a neutralizing anti-GDF15 antibody or knockdown GDF15 (with siGDF15) in CAFs. Furthermore, we also confirmed that the GDF15+ cells mainly co-localized with FAP, which was identified as the typical phenotype of CAFs in the BM stroma.ConclusionsWe firstly demonstrate that the functional CAFs are widespread within the BM of AML patients and should be a critical chemo-protective element for AML cells by producing amount of GDF15.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0405-0) contains supplementary material, which is available to authorized users.

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

“…Increased circulating MIC-1 has been reported as a pharmacodynamic effect of treatment with other MDM2 inhibitors in patients with relapsed/ refractory AML and in patients with other solid tumors. [15][16][17][18]41 Although MIC-1 has been shown to contribute to the chemoprotection of AML cells, 42 whether MIC-1 contributed to AML cell survival following treatment with AMG 232 in this study is unclear.…”

Acute Myeloid Leukemia and the Bone Marrow Niche—Take a Closer Look

“…Furthermore, cancer-associated fibroblasts are considered to influence the chemo-resistance of many solid tumors. Zhai et al presented that fibroblasts are increased in leukemic bone marrow and can provide chemo-protective elements for AML ( 49 ). Further animal experiments need to verify these findings.…”

GDF‐15 in solid vs non‐solid treatment‐naïve malignancies

“…For multiple myeloma, an increased survival of stroma‐dependent multiple myeloma cells at high levels of GDF‐15 linked to worse event‐free survival as well as an enhanced tumour‐initiating and renewal potential have been described . Moreover, an in vitro study reported GDF‐15 mediated protection of AML cell lines . Our data cannot confirm a general prognostic significance of GDF‐15 for haematological malignancies, yet a specific association of GDF‐15 in multiple myeloma cannot be excluded.…”

“…14,27 Moreover, an in vitro study reported GDF-15 mediated protection of AML cell lines. 28 Our data cannot confirm a general prognostic significance of GDF-15 for haematological malignancies, yet a specific association of GDF-15 in multiple myeloma cannot be excluded. It seems that GDF-15 overexpression and secretion is more characteristic for the solid tumour entities, indicating a different role of GDF-15 for cancerous cell lines of haematological malignancies.…”