An Orthotopic Model of Lung Cancer to Analyze Primary and Metastatic NSCLC Growth in Integrin α1-Null Mice

Abstract

The role of matrix metalloproteinase (MMP)9 in lung cancer progression is controversial. MMP9 promotes local tumor progression and distant metastasis in mouse models by enhancing extracellular matrix degradation, releasing VEGF from extracellular matrix and promoting vascular pericyte recruitment. Furthermore, increased plasma MMP9 expression levels in human subjects with metastatic non-small cell lung cancer (NSCLC) inversely correlates with survival. In contrast, MMP9 can benefit the host by generating inhibitors of endothelial cell proliferation such as angiostatin and NC1 domains of collagen IV. To better understand the role of host MMP9 on the primary growth and metastatic potential of NSCLC, we performed an orthotopic model of NSLC in integrin alpha1-null mice (a genetic model for increased MMP9). In these mice we observed decreased number, size and vascularization of primary NSCLC tumors when compared to wild type controls. In addition, decreased number and size of NSCLC-derived metastases were evident in the alpha1-null mice. Furthermore, pharmacological inhibition of MMPs in the alpha1-null mice at the time of tumor cell injection resulted in an increase in the number of both primary and metastatic lung cancer as compared to untreated mice, suggesting that primary growth and metastases of NSCLC are worsened by the early inhibition of MMPs. In conclusion, although MMP9 may potentially promote tumor growth and metastasis, production of MMP-dependent anti-angiogenic factors seems to override these effects and protects the host from NSCL growth and progression.

The integrin–collagen connection – a glue for tissue repair?

“…Reduced experimental tumorigenesis in lung cancer models (Chen et al, 2005;Macias-Perez et al, 2008).…”

“…2). Furthermore, the absence of α1 has been found to ameliorate or reduce tumor growth and metastasis in a number of lung cancer models (Chen et al, 2005;Macias-Perez et al, 2008). Careful investigation of the role of α1 in the colon has revealed that it is expressed on both epithelial cells and submucosal myofibroblasts (Boudjadi et al, , 2015.…”

“…(8) Trailblazer cells lead collective invasion and generate pathways within collagen matrices that also allow opportunist follower cells to invade. (12) α1β1 is expressed on tumor cells, and promotes tumor growth and metastasis (Chen et al, 2005). (13) α1β1 is also expressed on endothelial cells, where it promotes angiogenesis (Pozzi et al, 2000), and downregulates levels of active MMP-9, which suppresses the production of the angiogenesis inhibitor angiostatin.…”

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

“…7 Traditional microarrays using RNA from whole tumors cannot distinguish if genes are expressed from tumor cells or surrounding host cells, such as fibroblasts, endothelial cells, or inflammatory cells. The Hu/Mu ProtIn chip was designed to distinguish mouse and human proteases and protease inhibitors by generating oligonucleotides specific for either mouse or human genes.…”

“…The biotinylated cRNA (15 Ag) was fragmented and hybridized to a customized Affymetrix protease microarray containing 979 human and mouse genes. 7 Hybridized cRNA was detected using streptavidin coupled to phycoerythrin and visualized using a laser scanner. The image data were quantified to generate gene expression values and ratios of gene expression between the hybridized samples.…”