Solitary Lung Tumors and Their Spontaneous Metastasis in Athymic Nude Mice Orthotopically Implanted with Human Non-Small Cell Lung Cancer

Abstract

We examined the tumorigenic and metastatic potentials of three human non-small cell lung cancer (NSCLC) cell lines, PC-14, A549 or Lu-99 cell lines suspended in Matrigel-containing phosphate-buffered saline were orthotopically implanted into the lungs of nude mice. The formation of a solitary tumor nodule in the lung was observed after the implantation of all cell lines. Intrapulmonary implantation of PC-14 or Lu-99 cells resulted in spontaneous distant metastases. In contrast, A549 cells caused multiple intrapulmonary metastases to the right and left lobes of the lung without producing visible lymphatic metastasis. We also investigated the expression of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR) and c-MET in these cell lines in vitro and in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of MMP-2 and membrane-type 1 MMP (MT1-MMP) was elevated in PC-14 as compared with the other two cell lines. In contrast, stronger expression of c-MET was observed in A549 than in PC-14 or Lu-99. These results indicate that differential patterns of metastasis of lung cancer might be associated with differential expression of metastasis-associated molecules. Our orthotopic implantation models display clinical features resembling those of NSCLC, and may provide a useful basis for lung cancer research.

Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms

“…Using in vivo analysis, which allows to reveal not only autocrine but also paracrine effects, we found that in addition to deceleration of tumor growth, VEGF-C downregulation caused inhibition of lymphangiogenesis in tumor and surrounding tissues. To assess an influence of these effects on metastatic activity of cancer cells, we used a model of A549 orthotopic lung xenograft, capable to form metastasis in other lung lobes (Wang et al, 1992;Yamaura et al, 2000). We found that the number of lung metastasis in animals bearing A549 xenografts with inhibited VEGF-C expression was reduced about twofold.…”

Overexpression of Soluble TRAIL Induces Apoptosis in Human Lung Adenocarcinoma and Inhibits Growth of Tumor Xenografts in Nude Mice

“…Orthotopic Lung Cancer Model and Assessment of Growth. Orthotopic implantation of A549 cells was done as described by Yamaura et al (18). The left chests of anesthetized mice were incised and 20 AL aliquots of the A549 cell suspensions (5 Â 10 7 /mL), containing 1 mg/mL of Matrigel (BD Biosciences, Bedford, MA), were injected into the lung parenchyma through the intercostal space (f3 mm depth).…”

Antitumor immune activity by chemokine CX3CL1 in an orthotopic implantation of lung cancer model in vivo

“…Previous studies have showed that the biological behavior of cancer cells is influenced by the implantation organ (1), while properties of the immune system are also known to be different in each organ. A useful model for a solitary pulmonary tumor has previously been established by the intrapulmonary implantation of LLC cells in syngeneic immunocompetent mice (7,(19)(20)(21). This model has the advantage of being simple and easy regarding the implantation procedure with a small skin incision at a pre-determined site followed by direct puncturing through the intercostal space to the lung parenchyma, without thoracotomy or intubation.…”