Abstract
Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain.
Highlights
The most frequent presenting symptom of prostate metastasis to the skeleton is bone pain [1]
We examine whether a blocking antibody to nerve growth factor (NGF) may be therapeutically useful in attenuating bone pain, tumor growth, and tumor-induced bone remodeling due to a prostate tumor, which simultaneously induces significant bone formation and bone destruction
Whereas tumor metastasis to bone is common in lung, breast, and prostate cancers, prostate cancer is unique in that bone is often the only clinically detectable site of metastasis and prostate tumors tend to be primarily bone-forming rather than bonedestroying [25, 26]
Summary
The most frequent presenting symptom of prostate metastasis to the skeleton is bone pain [1] Pain originating from these bony metastases usually increases in intensity with the evolution of the disease and is commonly divided into three categories: ongoing pain, spontaneous breakthrough (incident) pain, and movementevoked breakthrough pain [2, 3]. Doi:10.1158/0008-5472.CAN-05-0826 cancer progresses, intermittent episodes of extreme pain can occur spontaneously, or more commonly, after weight-bearing or movement of the affected limb [4] Of these types of pain, breakthrough pain is the most difficult to control, as the dose of opioids required to control this pain are usually significantly greater than that needed to control ongoing pain and are often accompanied by significant unwanted side effects such as sedation, somnolence, respiratory depression, and constipation [4, 5]. This newly formed ‘‘woven’’ bone tended to isolate individual tumor-bearing compartments, which, when viewed radiologically, present the characteristic scalloped appearance seen in the bones of patients with prostate tumor metastases to the skeleton [6]
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