Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells.
Integrin alpha11 (ITGA11/alpha11) is localized to stromal fibroblasts and commonly overexpressed in non-small-cell lung carcinoma (NSCLC). We hypothesized that stromal alpha11 could be important for the tumorigenicity of NSCLC cells. SV40 immortalized mouse embryonic fibroblasts established from wild-type (WT) and Itga11-deficient [knockout (KO)] mice were tested for their tumorigenicity in immune-deficient mice when implanted alone or coimplanted with the A549 human lung adenocarcinoma cells. A549 coimplanted with the fibroblasts showed a markedly enhanced tumor growth rate compared with A549, WT, or KO, which alone formed only small tumors. Importantly, the growth was significantly greater for A549+WT compared with A549+KO tumors. Reexpression of human alpha11 cDNA in KO cells rescued a tumor growth rate to that comparable with the A549+WT tumors. These findings were validated in two other NSCLC cell lines, NCI-H460 and NCI-H520. Gene expression profiling indicated that IGF2 mRNA expression level was >200 times lower in A549+KO compared with A549+WT tumors. Stable short-hairpin RNA (shRNA) down-regulation of IGF2 in WT (WT(shIGF2)) fibroblasts resulted in a decreased growth rate of A549+WT(shIGF2), compared with A549+WT tumors. The results indicate that alpha11 is an important stromal factor in NSCLC and propose a paradigm for carcinoma-stromal interaction indirectly through interaction between the matrix collagen and stromal fibroblasts to stimulate cancer cell growth.
Zhu
Chang-Qi
CQ
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, ON, Canada M5G 2M9.
Popova
Svetlana N
SN
Brown
Ewan R S
ER
Barsyte-Lovejoy
Dalia
D
Navab
Roya
R
Shih
Warren
W
Li
Ming
M
Lu
Ming
M
Jurisica
Igor
I
Penn
Linda Z
LZ
Gullberg
Donald
D
Tsao
Ming-Sound
MS
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007335:Insulin-Like Growth Factor II; D039001:Integrin alpha Chains / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D006133:Growth Substances; C035170:IGF2 protein, human; C121535:ITGA11 protein, human; D039001:Integrin alpha Chains; D011506:Proteins; D007335:Insulin-Like Growth Factor II; D003094:Collagen