PDGFR Signaling Blockade in Marrow Stroma Impairs Lung Cancer Bone Metastasis

Abstract

Bone microenvironment and cell-cell interactions are crucial for the initiation and development of metastasis. By means of a pharmacologic approach, using the multitargeted tyrosine kinase inhibitor sunitinib, we tested the relevance of the platelet-derived growth factor receptor (PDGFR) axis in the bone marrow (BM) stromal compartment for the initiation and development of lung cancer metastasis to bone. PDGFRb was found to be the main tyrosine kinase target of sunitinib expressed in BM stromal ST-2 and MC3T3-E1 preosteoblastic cells. In contrast, no expression of sunitinib-targeted receptors was found in A549M1 and low levels in H460M5 lung cancer metastatic cells. Incubation of ST-2 and human BM endothelial cells with sunitinib led to potent cell growth inhibition and induction of apoptosis in a dose-dependent manner. Similarly, sunitinib induced a robust proapoptotic effect in vivo on BM stromal PDGFRb þ cells and produced extensive disruption of tissue architecture and vessel leakage in the BM cavity. Pretreatment of ST-2 cells with sunitinib also hindered heterotypic adhesion to lung cancer cell lines. These effects were correlated with changes in cell-cell and cellmatrix molecules in both stromal and tumor cells. Pretreatment of mice with sunitinib before intracardiac inoculation of A549M1 or H460M5 cells caused marked inhibition of tumor cells homing to bone, whereas no effect was found when tumor cells were pretreated before inoculation. Treatment with sunitinib dramatically increased overall survival and prevented tumor colonization but not bone lesions, whereas combination with zoledronic acid resulted in marked reduction of osteolytic lesions and osseous tumor burden. Thus, disruption of the PDGFR axis in the BM stroma alters heterotypic tumor-stromal and tumor-matrix interactions, thereby preventing efficient engagement required for bone homing and osseous colonization. These results support the notion that concomitant targeting of the tumor and stromal compartment is a more effective approach for blocking bone metastasis. Cancer Res; 71(1); 164-74. Ó2010 AACR.

Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma

“…But our findings are also consistent with other cellular properties induced by the APC/ EPCR axis, which have been found critical in metastasis and have not been dissected in this study, including heterotypic cellcell adhesion (8) or cell-matrix interactions (31). These functions were partially affected upon APC/EPCR binding in our microarray analysis (data not shown).…”

“…Tumor cells leaving the primary site require survival abilities in the bloodstream to overcome sheer stress in the circulation. In the target organ, the progression of metastasis is based on complex interactions that trigger signaling pathways in the tumor and its neighboring milieu, and modulate tumor cell survival and organ colonization (8,9). Secondary sites, such as bone, also impose stringent conditions (10), including low pH, high calcium, and mechanical stiffness of the extracellular matrix (10), which impair the development of micrometastasis (11,12).…”

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

“…30 When A549 cells were administered intracardiac, mice developed bone metastasis; however, tumor morphology and bone histomorphometry were not analyzed. 31 Freeley et al 32 performed direct intratibial injections of A549 cells; mice developed mixed osteolytic and osteoblastic lesions that were inhibited by overexpressing noggin in the cells and co-administration of RANKL-Fc. In contrast to the latter model, our A549 model resembles the human counterpart of the disease that is often associated with multiple rather than a single metastatic lesion.…”

Localized and metastatic myxoid/round cell liposarcoma

“…29 Our finding that PDGFR-b expression was higher in metastatic lesions compared with localized lesions is intriguing given its role in bone metastasis. 30 Considering the relatively high prevalence of MLPS bone metastasis and the availability of PDGFR-b inhibitors, this may be an attractive locus for further investigation.…”