Role of SLRPs in Bone Biology Multiple papers were published this year that summarized key features of SLRPs in skeletal disease. These reviews highlight the fact that biglycan is not needed for bone development but, rather, appears to play a role in skeletal aging. This was demonstrated using mice unable to make biglycan that were found to acquire early onset osteoporosis, osteoarthritis and ectopic bone in their tendons. Research performed in the MBBTS indicates that the underlying mechanisms are based on the paradigm that biglycan controls the activity of key growth factors including TGF-beta, BMP-2 and wnt-3a. Each of these growth factors has profound effects on bone and biglycan's location at the cell surface makes it well suited for such regulatory functions. The regulation of extracellular growth factors by biglycan subsequently influences skeletal progenitor cell fate ultimately influencing bone, cartilage and tendon differentiation and tissue formation. Biglycan also has important roles in regulating muscle cell function. It controls cell membrane architecture at synapses by binding and regulating several components including the dystrophin-membrane and urotrophin-membrane glycoprotein complexes (DGC and UGC respectively). Biglycan is also important for synapse stabilization, one of the earliest structures affected in diseases such as ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). The systemic administration of biglycan, showing cellular repair of the DGC and UGC complexes coupled with its ability to improve muscle health and function in a mouse model of musculodystrophy (MDX), makes it a promising new candidate to consider for treating neuromuscular and musculoskeletal diseases. WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone Being the second leading cause of cancer death in men of all races, prostate cancer is a major health concern for men. It has been proposed that most elderly men harbor traces of prostate cancer, and yet the molecular underpinnings of how and why the cancer progresses are still elusive. Like many other dangerous cancers, prostate cancer cells have a very high incidence of migrating from the primary tumor to distant sites where they are a more direct cause of morbidity and mortality. A frequent site for the metastasis of prostate cancer is to bone;however, when the cancer progresses to this stage, it is usually incurable. Therefore there is a critical a need to: 1) understand what factors contribute to the disease progression in the prostate, 2) understand how and why prostate cancers home to bone and, further, 3) devise new ways to prevent this complex and devastating process. The metastasis of prostate cancer can be an inefficient process and only a fraction of prostate cancer patients develop cancer that metastasizes to distant sites. By analyzing the early events that take place during prostate cancer progression it is feasible that new diagnostic procedures could be developed that predict the progression and future severity of the cancer and optimize the timing and nature of therapeutic interventions. New information about candidate proteins involved in this process could, also, potentially be used to develop new therapies to reduce the spread and establishment of the disease at distant sites such as bone. WISP1 (wnt induced secreted protein-1) is a member of the CCN family that is named from its founding members of Cyr61/CCN1, CTGF/CCN2 and Nov/CCN3. There are currently six members of the family that also include WISP1/CCN4, WISP2/CCN5 and WISP3/CCN6. WISP1 was first identified as a gene expressed in the metastatic melanoma line, K-1735, where it was called Elm1 (referring to its expression in poorly metastatic cells). Around the same time that Elm1 was discovered, WISP1 was identified in a separate laboratory where it was found to be up-regulated by wnt1 transformed mammary epithelial cells, and in various colon cancer lines, as well as being expressed in human colon cancer tissue. Subsequently, WISP1 was shown to confer oncogenic features to rat kidney cells (NRK-49F), including accelerated growth, enhanced saturation density and increased ability to form tumors in mice. Since its original identification, WISP1 has been found in a variety of cancers, including esophageal squamous cell carcinoma, chondrosarcoma, breast carcinoma, neurofibromatosis type I, colorectal carcinoma, Lewis lung carcinoma, invasive cholangiocarcinoma, scirrhous gastric carcinoma and endometrial endometriod adenocarcinoma. Interestingly, WISP1 expression in many of these cancers is localized to the stromal tissues surrounding the cancerous cells, suggesting that it could play a role in the microenvironment that supports the growth and/or eventual spread of the primary tumor. In non-pathological conditions, WISP1 is found in several embryonic and adult tissues that notably include new sites of bone formation, where it appears to control osteogenesis. Considering the fact that prostate cancers have a high tropism to bone and, further, that this process can be enhanced by increasing bone turnover, we hypothesized that WISP1 may, potentially, be involved in regulating prostate cancer metatasis. This study was undertaken to first determine if and where WISP1 is expressed in primary prostate tumors and then, to determine the role of WISP1 in the growth and homing of prostate cancer cells to skeletal tissue. Our experiments show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model, TRAMP, in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested, it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.

Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2013
Total Cost
$1,444,402
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
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