An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells

Abstract

Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFβ strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFβ signaling. Although TGFβ transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFβ, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.

Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

“…We have also shown that PI3K/Akt signaling pathway, which is activated by heregulin, contributes to the maintenance of CSCs in breast cancer [101] . Insulin-like growth factor-2 (IGF-2) [102] and growth differentiation factor 15 (GDF15) [103] , downstream factors of heregulin/PI3K/Akt, have been shown to play important roles in CSC maintenance [ Figure 4]. MAPK-ERK signaling pathway is also important for CSC maintenance.…”

Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T-Helper Type 2 Cytokines

“…The STAT6 pathway is important for maintaining cellular metabolism, particularly oxidative mitochondrial metabolism. However, GDF15 increases transcriptional regulation in response to various cellular stress and metabolic changes associated with mitochondrial dysfunction (41)(42)(43)(44). Based on these findings, we speculate that metabolic changes caused by STAT6 KO are associated with increased blood levels of GDF15.…”

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

“…GDF15 (also known as MIC-1, NAG-1, PLAB, PTGFB) is a cytokine of the TGF-β superfamily that is up-regulated in response to inflammation, cardiovascular disease, obesity, and cancer [40][41][42]. GDF15 may be involved in the proliferation, migration, invasion, and angiogenesis of tumors, with with recent research finding GDF15 promoted EMT and invasion of breast cancers [43], and supported the maintenance of breast cancer stem-like cells [44]. Furthermore, GDF15 promoted the proliferation of cervical cancer cells by interaction with ErB2 to activate PI3K/AKT and MAPK/ERK pathways [28], and enhanced the migration of pancreatic cancer cells via an AKT pathway [29].…”