Matrix Metalloproteinase-9 from Bone Marrow–Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment

Abstract

The role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow-derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer-derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

“…Our data do not exclude the interpretation of previous studies, stating the great effect of host cell -derived gelatinases on aspects of tumor progression (8,9,12,28,34,43). In addition to this possibility, we could now attribute an important function to tumor cell -derived gelatinases, as well as assign distinct roles in invasion (mainly a function of MMP-9) and outgrowth of metastases (mainly a function of MMP-2).…”

“…In the clinical context, MMP-2 may directly affect tumor cell proliferation, maybe via MMP-2 -mediated release of growth factors bound in the extracellular matrix. Regarding MMP-9, other groups have provided evidence for a role of MMP-9 in establishment or angiogenesis of tumors at secondary sites (28); however, angiogenesis is not a crucial variable in our fast tumor model (25). Our results clearly indicated that tumor cell -derived MMP-9 determined the metastatic potential of tumor cells by promoting tumor cell invasiveness.…”

“…The benefit of knockout mice is to create a situation with optimal inhibition of the respective gene function, which may then lead to estimations about possible future therapies. Deficiency of MMP-2 in mice led to reduction of experimental metastasis to the lung (27) or inhibited tumorigenesis of intradermally implanted carcinoma or melanoma cells (28). Knockout of MMP-9 revealed that hostderived MMP-9 contributes to metastasis of melanoma or lung carcinoma cells (29), angiogenesis (30-32), or spontaneous metastasis by establishing a prometastatic niche (33).…”

“…This assay mimics invasive liver metastasis in a syngeneic and immunocompetent host (40,41). Immunocompetence is of high importance, as it was shown that host immune cells can also contribute to the levels of gelatinases in the tumor-host interface during metastasis (28,32,34,42,43).…”

Origin of carcinoma associated fibroblasts

“…[115][116][117][118] The fibroblast response is hardwired in the genome as part of the cancer's resemblance to a chronic wound, aiming at support of epithelial cell survival and expansion. [119][120][121][122][123][124][125][126][127][128] In addition to parsimony, this hypothesis offers clear predictions to scientifically test against corresponding null hypotheses; (1) That co-culture of cancer cells with normal fibroblasts will induce expression of CAF-specific genes in the fibroblasts, [63][64][65][66][67][68][69][70][71] [63][64][65][66][67][68][69][70][71] Many of the genes shown to be activated in these co-cultures are known markers of CAFs in vivo, such as MMP1, MMP3, collagens, TNC, etc. Evidence that this reciprocal interaction promotes cancer includes the anti-cancer effect of Imatinib, on carcinoma animal models.…”