Bone microenvironment and metastasis

Bone-derived S1P in the dialogue between bone cells and prostate cancer cells


A characteristic trait of prostate cancer is its ability to metastasize to bone as the disease progresses with a bone-forming (osteoblastic) phenotype, which is the result of stimulation of osteoblasts. Most patients with advanced prostate cancer will experience complications - known as skeletal-related events (or SREs) - from bone metastases that are currently incurable. Bone metastatic prostate cancer cells grow at a more rapid rate than primary prostate cancer, suggesting they are able to form a synergistic relationship with bone microenvironment, creating favorable conditions for their growth. A number of studies show that osteoblasts seem to be essential for tumor progression but only few osteoblast-derived factors such as interleukin-6 (IL-6), transforming growth factor-β (TGF-β) or insulin growth factor I (IGF-I) have been thus far described as growth factors able to stimulate proliferation of prostate cancer cells.


Our previous studies established that S1P induces prostate cancer cell proliferation and resistance to therapeutics including docetaxel-based chemotherapy, irradiation or androgen privation (Brizuela et al., 2012; Dayon et al., 2009; Pchejetski et al., 2010; Pchejetski et al., 2008; Pchejetski et al., 2005). Notwithstanding that S1P has been reported to regulate remodeling in normal bone physiology, its role in the pathological context of bone metastasis has not been described prior to our study. Because we have previously shown that the SphK1/S1P signaling was markedly expressed in osteoblastic MC3T3 cells and up-regulated by androgens (Martin et al., 2010), we investigated the potential role of S1P in the complex interactions between prostate cancer and osteoblastic cells.

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SphK1 is highly expressed in human and mouse osteoblastic cells, which secrete large amounts of S1P
Left Panel, basal SphK1 activity was quantified in various cancer cell lines (prostate, breast, lung, pancreas, neuroblastoma, leukemia), in non-differentiated osteoblastic MC3T3 cells and primary osteoblasts from mouse calvaria (mOB) or primary human femoral head osteoblastic cells (hOB).
Right panel, S1P levels were quantified in media from C4-2B and PC-3 prostate cancer cells, from non-differentiated osteoblastic MC3T3 cells and primary mouse calvaria osteoblastic cells (mOB) or from primary human femoral head osteoblastic cells (hOB).



In this work, we showed that bone microenvironment (osteoblasts) is a source of S1P and can promote cell proliferation and survival of cancer cells. S1P-borne osteoblast stimulates proliferation of metastatic prostate cancer cells and protects them from conventional therapeutics (chemotherapy and radiotherapy). S1P receptor subtype 1 (S1P1) expressed on prostate cancer is important for cancer cell responses to the S1P secreted by osteoblastic cells. S1P has a dominant effect as a paracrine growth factor as a substantial inhibition of osteoblast-derived effects are negated by interferring with S1P signaling.
In the bone microenvironment, prostate cancer cells produce factors that promote the growth and differentiation of osteoblastic cells into mature osteoblasts, which in turn further stimulate prostate cancer cell growth. It is important to note that we showed that SphK1/S1P signaling is critical during differentiation to mature osteoblasts, notably by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation.

Interestingly, the pattern of expression of S1P receptors appeared to be modified during the differentiation of osteoblasts with a decrease in S1P1 and S1P2 expression contrasting with a relative increase in S1P3. Importantly, the more osteoblastic cells were differentiated into mature osteoblasts, the more S1P signaling was up-regulated and the more proliferation of prostate cancer cells was stimulated, suggesting that osteoblastic SphK1/S1P signaling may be central in the molecular mechanism driving the vicious interaction between osteoblastic and prostate cancer cells in bone metastasis.

In summary, together with other osteoblast-related growth factors,
S1P-borne osteoblast cells can participate in the development of metastasis and resistance to therapy. Bone metastasis is a lethal form of prostate cancer and presents considerable challenges for treatment. Interfering with the interactions between prostate cancer cells and aspects of the bone microenvironment may hold the key to preventing the development of bone metastases or resensitize to therapeutics, and S1P may be a candidate as a target in the treatment of prostate cancer bone metastasis.
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Brizuela et al, Mol Oncol, 2014