Prostate Cancer and Prostatic Diseases (2000) 3, 6±12 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $15.00 www.nature.com/pcan Review Cell adhesion and chemotaxis in prostate cancer metastasis to bone: a minireview CR Cooper1* & KJ Pienta1 1University of Michigan Comprehensive Cancer Center, Department of Internal Medicine, Ann Arbor, MI 48109, USA Bone metastasis is a common phenomenon in patients with advanced prostate cancer. The molecular and cellular mechanisms involved in this process are not well understood. Past reviews on this subject primarily focused on prostate tumor growth in the bone marrow and the effects this growth has on bone homeostasis (ie osteoblastic and osteolytic). Cell chemotaxis and adhesion are also important for site-speci®c metastasis. In this review we have focused on chemotactic and cell adhesion molecules potentially involved in prostate cancer metastasis to bone. In addition, recently developed animal models for prostate cancer metastasis to bone are discussed. Prostate Cancer and Prostatic Diseases (2000) 3, 6±12. Keywords: cell adhesion molecules; cytokines; human bone marrow endothelial cells; chemoattractants; prostate cancer cells Introduction cells.7 The inactivation of parathyroid hormone-related protein (PTH-rp) by prostate-speci®c antigen may pro- Prostate cancer bone metastasis is a major clinical prob- mote the osteoblastic reaction seen in prostate cancer lem and is commonly associated with intractable pain, patients. Yoneda has proposed that the minor osteolytic pathological fracture and spinal cord compression.1 Pre- reaction observed in bone lesions of prostate cancer vious reviews of prostate cancer metastasis have focused patient is due to cross-talking between metastatic prostate predominately on tumor growth in the bone microenvir- cancer cells, osteoblasts and osteoclasts.3 The activation of onment and the effects that tumor growth has on bone osteoclasts causes bone resorption and provides space, homeostasis (ie osteoblastic and osteolytic).2,3 The growth calcium, and bone-derived growth factors that are needed rate of prostate cancer cells accelerates once they enter the for the ensuing osteoblastic reaction. In addition, these bone environment, suggesting that factors are present in growth factors can further stimulate prostate tumor pro- bone that stimulate tumor proliferation. Bone ®broblast- liferation.3 The scenario is different in breast cancer derived factor and transferrin are two of several mole- because the predominate effect is osteolytic. Breast cules that have been shown to be mitogenic for prostate cancer cells produce PTH-rp, which is a potent activator cancer cells.4,5 A recent article by Koeneman et al, of osteoclasts promoting bone destruction. Bone-derived- hypothesized and demonstrated that prostate cancer growth factors are then released, such as transforming cells propagate well in bone because they acquire osteo- growth factor-beta (TGF-b). TGF-b can further stimulate mimetic properties.6 Using the LNCaP animal model breast tumors to produce PTH rp, creating a vicious cycle system, the authors demonstrated that the progression in the bone proper.3,8 of prostate cancer mimics the maturation of osteoblast Cell chemotaxis, cell adhesion, and selective tumor growth at preferred sites are three important steps required for site-speci®c metastasis (Figure 1).9 As out- lined above, the data regarding tumor growth in bone has *Correspondence: CR Cooper, Department of Internal Medicine, been reviewed extensively and therefore the focus of this University of Michigan Comprehensive Cancer Center, 1500 E. article is to review the data on potential chemotactic and Medical Center Drive, Ann Arbor, MI 48109-0946, USA. E-mail: [email protected] cell adhesion molecules responsible for bone metastasis. Received 8 November 1999; revised 15 February 2000; accepted In addition, recent developments and advancements in 16 February 2000 animal models for bone metastasis will be discussed. Cell adhesion and chemotaxis CR Cooper and KJ Pienta colonizing tumor cells.12 This hypothesis was tested 7 using an in vitro system of differentiating osteoblasts. The data demonstrated that osteoblast products found in conditioned media were able to attract breast and melanoma tumor cells. In addition, osteoblast-condi- tioned media stimulated production of matrix metallo- proteinases in cancer cells. These activities were most pronounced with conditioned media obtained during the nodule formation and premineralization phases of bone matrix formation. These results suggest that pro- ducts secreted by osteoblast during bone remodeling can serve as potent chemoattractant molecules for circulating breast and melanoma tumors. An early study conducted by Mundy et al identi®ed collagen I as a chemoattractant for Walker rat tumor (clone 4), HeLa cells and human breast cancer cells (MB- MDA-231).13 A similar effect was observed by synthetic di- and tri-peptides that contained amino acid predomi- nately present in collagen helix. Also, the collegenase treatment of bone liberated chemotactic molecules for tumor cells.14 Another study demonstrated that tumor cells can secret enzymes to liberate collagen I from bone.15 Bone metastasizing PC-3 ML cells were injected into the bone medullary cavity of SCID mice femurs both in vivo and following isolation in vitro. The amount of collagen I Figure 1 Proposed model for chemotaxis and cell adhesion in prostate released in the bone marrow and the blood plasma was cancer metastasis to the bone. Prostate cancer cells (CaP) in the bone determined by ELISA and was a function of time of marrow microvessel are attracted to the bone matrix by chemotactic factors incubation and number of cells injected in the femurs. (ie osteonectin, TGF-b, IGF-I and II, EGF).16,17 The prostate cancer cell initially interacts with a selectin molecule (ie galectin-3), and then an The extent of collagen I released correlated with MMP-2 intregin like molecule (ie LFA-1) on the apical side of the human bone and -9 secretion in the bone medullary. The amount of marrow endothelial (HBME) cells.26 This interaction of the cancer cell with MMP-2 and -9 released was determined by ELISA. endothelium results in extravasation of the cancer cell from the circula- Because the bone matrix is mostly composed of type I tion.24 The abundance of TGF-b in the bone microenvironment stimulates collagen, which is enzymatically degraded during the the prostate cancer cell to express a2b1 (collagen I receptor) as they interact process of bone resorption and tumor in®ltration, these with osteablast cells.3,37 Finally, the prostate cancer cell adheres to the bone matrix which is in primarly composed of collagen I. The release of growth collagen fragments could play a biological role in bone- factors from the bone matrix by osteoclast activity stimulates cell division directed metastasis in vivo.14,15 and ultimately tumor growth in the bone.3,9,11 Adapted from Alberts Human epidermal growth factor (hEGF) has been et al.48 identi®ed as a chemoattractant for the human prostate tumor cell line TSU-pr1 (Table 1).16 Secretory proteins produced from cell lines MG-63 (osteosarcoma), SK-ES-1 Chemoattractants (Ewing's sarcoma), and KG-1 (leukemia) promoted che- momigration of TSU-pr 1 prostate tumor cells in a dose- The dissemination of tumor cells to speci®c organs may dependent manner in Boyden chambers. Various cyto- be directed, in part, by chemoattractants.10 Hujanen and kines normally present in bone and lymph nodes were Terranova investigated the ability of a variety of tumor evaluated as possible chemotactic agents for TSU-pr 1, cells to migrate to extract derived from organs primarily which included interleukin-1 alpha, interleukin-2, inter- targeted for metastasis.10 Using a Boyden chamber assay, leukin-6, tumor necrosis factor-beta, transforming growth it was demonstrated that B16-Br2 melanoma cells, which factor-beta, interferon alpha 2-a, EGF and granulocyte- metastasize to the brain, migrated more to brain derived macrophage colony-stimulating factor. Only EGF was extract. Lung extract preferentially attracted lung metas- shown to stimulate chemomigration of the prostate tasizing T241-PM2 ®brosarcoma cells. Murine M50 ± 76 tumor cell line through the Boyden chamber in a dose- reticulum cell sarcoma cells, which metastasize to liver and ovaries, selectively migrated more to liver extract, while bone and brain metastasizing MCF-7 breast adeno- Table 1 Potential chemotactic agents involved in prostate cancer carcinoma cells migrate mostly to both bone and brain metastasis to bone extracts. This data suggests that tissues contain speci®c chemotactic factors for tumor cells that preferentially Chemotactic agents References metastasize to them. EGFa 16 Bone is constantly being remodeled and subsequently TGF-bb 18 releases potential chemoattractive molecules for exposure IGF-Ic 19 to circulating tumor cells (Figure 1).9,11 It was hypothe- IGF-IId sized that osteoblast products, directly secreted or Osteonectin 20 released from the bone matrix by osteoclasts resorbing aEpidermal growth factor. bTransforming growth factor-beta. cInsulin growth activity, are potential chemoattractive agents for bone factor-I. dInsulin growth factor-II. Prostate Cancer and Prostatic Diseases Cell adhesion and chemotaxis CR Cooper and KJ Pienta 8 dependent manner. This chemomigration was inhibited speci®c tumor cell adhesion. The data for this investiga- by treatments with monoclonal antibody to hEGF recep-