Bone Microenvironment Promotes Bone Metastases in Prostate Cancer

Evan T. Keller, DVM, PhD

Targeting the bone microenvironment appears to be a potential approach to treating prostate cancer, according to Evan T. Keller, DVM, PhD, professor at the University of Michigan Health System in Ann Arbor.

Keller’s talk focused on the unique properties of the bone microenvironment that foster the development of prostate cancer metastasis. These properties include a combination of factors that cause prostate cancer cells to migrate and attach to bone and enhance their ability to thrive in the bone microenvironment.

Speaking at the recent ASCO 2012 Genitourinary Cancers Symposium, Keller reviewed the pathobiology of prostate cancerinduced bone metastasis, and he highlighted potential targets for interventions to alter the bone environment so that prostate cancer becomes more resistant to metastasis and less resistant to chemotherapy.

“Cellular and soluble bone components impact bone metastasis. Targeting the microenvironment may add to our ability to impact metastasis. The answer to the question of whether the bone microenvironment is important is that bone matters,” Keller emphasized.

Two fundamental concepts related to this research are: Prostate cancer selectively targets the bone, and bone metastasis can be clinically dormant. That’s why prostate cancer patients can present as low-risk, but years later develop bone metastases that are clinically silent.

Prostate cancer is selective to the bone and seems to favor the axial skeleton. Most of the tumors are osteoblastic, inducing increased areas of bone production. However, a mixture of blastic and lytic activity has been shown in the bones of patients with prostate cancer.

The potential importance of the microenvironment was first put forth in 1889 by Stephen Paget, with the “seed [cancer cell] and soil [bone environment]” hypothesis. This hypothesis is now in the forefront, Keller said.

“Clinical and experimental evidence suggests bone offers a unique opportunity for prostate cancer growth,” he explained.

Among the cells that can be implicated in bone metastasis are bone marrow cells, mesenchymal cells, and hematopoietic stroma and adipocytes.

A major focus of research is identifying factors that attract cancer cells to the bone. The stromalderived factor (SDF) receptor CXCR4 is one of those factors. SDF promotes migration of cancer cells, and blocking this pathway blocks migration in the mouse model. Collagen type I is another factor that acts as an attractant and proinvasive mediator of cancer cells to the bone.

Dormancy of bone metastasis may be induced when cancer cells target and bind to osteoblasts. A recent study showed that cancer cells compete with hematopoietic stem cells to target osteoblasts, Keller explained.

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Cellular and soluble bone components impact bone metastasis. Targeting the microenvironment may add to our ability to impact metastasis. ”

—Evan T. Keller, DVM, PhD

Translational experiments are being considered to release the dormant cells and allow cycling to occur, thus making the cells vulnerable to chemotherapy.

Several osteoblast-derived factors induce prostate cancer proliferation, and they induce a bone metastatic phenotype. Gene array testing identified 35 genes with a bone metastatic signature. This is evidence that osteoblasts are likely to promote bone metastatic activity in prostate cancer, he continued.

During the vicious cycle of osteolytic metastases, bone resorption releases a variety of growth factors that can enhance prostate cancer proliferation, such as the Wnt pathway. Prostate cancer cells express Wnt, Keller said. “Metastatic prostate cancer expresses a variety of osteolytic factors that causes release of growth factors to the bone, leading to an osteoblastic phase.”

If the bone does indeed support prostate cancer growth, therapies targeted to the osteoblastic process might be useful, he suggested. “The osteoblastic side has been neglected [in developing bone-targeted therapies].”

There is some concern that although dormancy and a lack of cell cycling can make cancer cells resistant to chemotherapy, activating cell cycling may make the cells less resistant to chemotherapy but could also promote cancer growth.

Clearly, more research is needed on potential therapies targeted to the bone microenvironment, and for the moment, this is an active area of study.