Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo

Abstract

Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc + ) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis. IntroductionMicrometastases, persisting in various tissues of cancer patients after removal of the primary tumor, represent the pathophysiologic basis for cancer relapse as overt metastases. Preferential colonization of certain tissues by cancer cells and their subsequent growth are determined by interaction with the tissue-specific microenvironment (1, 2). Therefore, pharmacologic interference with the microenvironmental growth support is becoming an attractive therapeutic strategy for repressing metastatic tumor growth (3).Bone metastases are common in breast and prostate cancer and cause considerable morbidity (4-9). Evidence from animal studies and more recently of human studies supports the concept that the rate of bone remodeling is directly related to the occurrence and progression of bone metastases (10-15).The skeleton is a highly dynamic tissue that is continuously renewed through the process of bone remodeling. This occurs at multiple sites in the skeleton by temporary structures called basic multicellular units (BMU; refs. 16,17). The number and the activity of these BMUs determine the rate of bone turnover (18). During bone remodeling, osteoblasts and osteoclasts, the cellular components of the BMU, secrete paracrine factors that induce chemotaxis and cell adhesion, support cell survival and growth,...

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

“…As expected (van der Pluijm et al, 2005;Buijs et al, 2007a), vehicle-treated cells readily formed multiple detectable bone metastases (Figures 5a-c).…”

“…The animal experiments were approved by the local committee for animal health, ethics and research of Leiden University and conducted in accordance with the European Communities Council Directive 86/609/EEC. BMP2-, BMP7-, BM2/7-or vehicle-pretreated MDA-MB-231/Luc þ cells (van der Pluijm et al, 2005) were harvested at 70-80% confluence. A single-cell suspension of 10 5 cells/100 ml of phosphate-buffered saline was injected into the left cardiac ventricle and cancer cell growth was monitored weekly by whole body bioluminescent imaging (BLI) using an intensified charge-coupled device (I-CCD) video camera of the in vivo Imaging System (IVIS100; Xenogen, Alameda, CA, USA) as described previously (Buijs et al, 2007a;.…”

Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer

“…Similarly, treatment with olpadronate, another bisphosphonate, demonstrates that the tumour burden in the initial phases is more heavily impacted and returns to vehicle- treated levels by the end of the 47-day treatment. During the same time frame, radiography shows a sustained and extensive decrease in osteolytic lesions (van der Pluijm et al, 2005), thus substantiating the primary mechanism of action of bisphosphonates as anti-resorptive. We observed primarily a large reduction in boneassociated soft tissue tumour burden (93%) after administration of zoledronate.…”

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

“…Surgical and analytical procedures were performed while mice were anesthetized. 29,31,32 Intraosseous Inoculation of PC-3M-Pro4/luc ϩ Cells A single cell suspension of PC-3M-Pro4/luc ϩ cells was injected into the right tibiae. 29 -31 The progression of cancer cell growth was monitored weekly by BLI.…”