Bone secreted factors induce cellular quiescence in prostate cancer cells

Abstract

Disseminated tumor cells (DTCs) undergo a dormant state in the distant metastatic site(s) before becoming overt metastatic diseases. In prostate cancer (PCa), bone metastasis can occur years after prostatectomy, suggesting that bone may provide dormancy-inducing factors. To search for these factors, we prepared conditioned media (CM) from calvariae. Using live-cell imaging, we found that Calvarial-CM treatment increased cellular quiescence in C4-2B4 PCa cells. Mass spectrometry analysis of Calvarial-CM identified 132 secreted factors. Western blot and ELISA analyses confirmed the presence of several factors, including DKK3, BMP1, neogenin and vasorin in the Calvarial-CM. qRT-PCR analysis of total calvariae versus isolated osteoblasts showed that DKK3, BMP1, vasorin and neogenin are mainly expressed by osteoblasts, while MIA, LECT1, NGAL and PEDF are expressed by other calvarial cells. Recombinant human DKK3, BMP1, vasorin, neogenin, MIA and NGAL treatment increased cellular quiescence in both C4-2b and C4-2B4 PCa cells. Mechanistically, DKK3, vasorin and neogenin, but not BMP1, increased dormancy through activating the p38MAPK signaling pathway. Consistently, DKK3, vasorin and neogenin failed to induce dormancy in cells expressing dominant-negative p38αMAPK while BMP1 remained active, suggesting that BMP1 uses an alternative dormancy signaling pathway. Thus, bone secretes multiple dormancy-inducing factors that employ distinct signaling pathways to induce DTC dormancy in bone. The majority of men who die of prostate cancer (PCa) have bone metastasis 1. Bone metastasis can occur years or decades after prostatectomy 2 , suggesting that disseminated tumor cells (DTCs) had been dormant at the metastatic site in bone 3. Tumor dormancy is now been considered a critical step in the process of metastatic progression during which tumor cells escape therapies that target tumor cells. Dormant tumor cells can become a significant problem at a later time when tumor cells exit dormancy. Tumor dormancy can be due to instrinsic properties of tumor cells 4 or due to tumor microenvironment that provides conditions for tumor cells to enter into a quiescent state 3. In PCa, the bone microenvironment likely plays a critical role in tumor dormancy as bone is the major site of tumor recurrence. How the bone microenvironment promotes DTCs to enter a transient dormant state in bone remains unclear. It is likely that dormancy versus progression of PCa in bone depends on the dynamic interactions between PCa cells and cellular components in bone 5. Using intravital microscopy, Lawson et al. 6 showed that myeloma cells are dormant when they are in close proximity with the endosteal bone surface in the tibia, but reactivate when they move further away from bone. Wang et al. 7 showed that PCa cells that home to bone are frequently associated with osteoblast lineage cells. Thus, it is likely that the bone microenvironment, especially osteoblasts, are providing dormancy-inducing factors. Identification of factors in the bone microenvironment tha...

Targeting the RANKL/RANK/OPG Axis for Cancer Therapy

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Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

“…High BMP1 levels predict poor survival in cancers such as renal clear-cell carcinoma (ccRCC) 35 but predict better survival in breast cancer 36 . BMP1 enhances malignancy of hepatocellular carcinoma 37 and ccRCC 35 , promotes cancer cell motility in gastric cancer 38 , but induces cellular quiescence in prostate cancer cells 39 . Here, we showed that BMP1 can suppress tumor growth and metastasis in PDAC models by promoting fibrillar collagen deposition, but only in cancer cells expressing substantial amounts of collagen.…”

Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

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