Bone cancer pain

Abstract

In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism-based therapies to treat the cancer pain. Several of these mechanism-based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.

Figure 1

Development of a mouse model of bone cancer pain and disease progression. Low-power anterior–posterior radiograph of a mouse femur showing the unilatereal injection of sarcoma cells into the femur (A) and confinement of the tumor cells in marrow space with an amalgam plug (B). The present model allows a simultaneous visualization and quantitative evaluation of the tumor burden by using 2472 sarcoma cancer cells genetically manipulated to express enhanced green fluorescent protein (GFP). (C) GFP-transfected tumor cells (green) injected into the ipsilateral femurs at day 6 (arrow), day 10, and day 14 postinjection. Scale bar: 6 mm in (A, B) and 1.5 mm in (C).

Figure 2

Bone remodeling and tumor growth in the 2472 sarcoma and ACE-1 prostate carcinoma-injected femurs have different characteristics depending on the osteolytic or osteoblastic component of the tumor cells as assessed by µCT imaging and hematoxilin and eosin (H&E) staining. Sham-injected femurs present relative absence of bone formation or bone destruction (A, D). The 2472 sarcoma-injected femurs display a primarily osteolytic appearance visible as regions absent of trabecular bone at the proximal and distal heads (B) as well as replacement of normal hematopoietic cells by tumor cells (E). The ACE-1 prostate carcinoma-injected femurs mainly present an osteoblastic appearance which is characterized by pathologic bone formation in the intramedullary space (C) surrounding pockets of tumor cells which generate diaphyseal bridging structures (F). (A–F) Scale bar: 0.5 mm. T, tumor; H, normal hematopoietic cells; WB, ACE-1-induced woven bone formation.

Figure 3

Schematic showing factors in bone (A) and receptors/channels expressed by nociceptors that innervate the skeleton (B) that drive bone cancer pain. A variety of cells (tumor cells and stromal cells including inflammatory/immune cells, osteoclasts, and osteoblasts) drive bone cancer pain (A). Nociceptors that innervate the bone use several different types of receptors to detect and transmit noxious stimuli that are produced by cancer cells (yellow), tumor-associated immune cells (blue), or other aspects of the tumor microenvironment. There are multiple factors that may contribute to the pain associated with cancer (B). The transient receptor potential vanilloid receptor-1 (TRPV1) and acid sensing ion channels (ASICs) detect extracellular protons produced by tumor induced tissue damage or abnormal osteoclast-mediated bone resorption. Tumor cells and associated inflammatory (immune) cells produce a variety of chemical mediators including prostaglandins (PGE2), nerve growth factor (NGF), endothelins (ET-1) and bradykinin (BK). Several of these proinflammatory mediators have receptors on peripheral terminals and can directly activate or sensitize nociceptors. It is suggested that movement-evoked breakthrough pain in cancer patients is partially due to the tumor-induced loss of the mechanical strength and stability of the tumor-bearing bone so that normally innocuous mechanical stress can now produce distortion of the putative mechanotransducers (TRPV1, TRPV4, and TRPA1) that innervate the bone.

Figure 4

Osteoprotegerin (OPG) attenuates sarcoma-induced bone destruction in a mouse model of bone cancer pain. (A) Low-power frontal radiograph of mouse pelvis and hind limbs following unilateral injection of 2472 murine osteosarcoma cells into the distal end of the femur and closure of the injection with a dental amalgam plug (arrow). The amalgam plug was used to prevent tumor cells from growing outside the bone. High-resolution radiographs of sham-injected (B and D) and sarcoma-injected (C and E) femurs from mice that received vehicle (B and C) or OPG (D and E). Note that at day 17 after the injection of the osteosarcoma cells, there is significant bone destruction in the distal femur without OPG (C; white arrowhead), whereas tumor induced bone destruction is not evident in sarcoma-injected mouse that received OPG (E). Scale bars represent 10 mm (a) and 0.5 mm (b–e; bottom panel). (With permission from Honore, P. et al.)

Figure 5

Anti-NGF attenuates spontaneous bone cancer pain in a model where the tumor cells (canine prostate cells) do not express NGF. Anti-NGF treatment (10 mg/kg, i.p., given on days 7, 12, and 17 posttumor injection) attenuated ongoing bone cancer pain behavior on days 7–19 posttumor injection. In these experiments, canine prostate carcinoma (ACE-1) cells were injected into the femur of adult male mice. The time spent guarding (A) and number of spontaneous flinches (B) of the afflicted limb over a 2-minute observation period were used as measures of ongoing pain. Anti-NGF significantly reduced ongoing pain behaviors in tumor-injected mice as compared with ACE-1 + vehicle. Note that ACE-1 cells in vitro express undetectable levels of NGF mRNA or protein, suggesting that NGF could be released mainly from tumor-associated macrophage and immune cells. Bars represent mean S.E.M. *P < 0.05 versus sham + vehicle; ^#P < 0.05 versus ACE-1 + vehicle. (With permission from Halvorson, K.G. et al.)