Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression.
In human carcinomas, stromelysin-3/matrix metalloproteinase 11 (ST3, MMP11) expression by nonmalignant fibroblastic cells located in the immediate vicinity of cancer cells is a bad prognostic factor. Using mouse models of primary tumors, it has been demonstrated that ST3 is a key player during local invasion, favoring cancer cell survival in connective tissue through an antiapoptotic function. To investigate the ST3 impact on additional phases of cancer cell invasion, we developed mammary gland cancer prone MMTV-ras transgenic mice in wild-type (ras+/+;ST3+/+) or ST3-deficient (ras+/+;ST3-/-) genotype and studied their whole natural cancer history. The tumor-free survival and delay between the first ras oncogenic hit and primary tumor appearance increased in ras+/+;ST3-/- mice (P < 0.000001 and <0.0000007, respectively). A systematic search for occult primary tumors and metastases revealed, in addition to a lower total number and size of primary tumors (P < 0.02), an unexpected higher number of metastases (P < 0.01) in ras+/+;ST3-/- mice. Moreover, for a similar number and size of primary invasive tumors, ras+/+;ST3-/- mice developed more metastases, indicating that the cancer cells evolving in ST3-deficient stroma have an increased potential to hematogenous dissemination. We conclude that the ST3 microenvironment is a consistently active partner of invading cancer cells but that its function differs throughout cancer progression, being tumor enhancer or repressor in processes leading to local or distal invasion. Such a dual effect for an MMP might shed light, at least partially, for the absence of survival benefit for patients included in anti-MMP clinical trials.
Andarawewa
Kumari L
KL
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale U184/ULP BP 163, 67404 Illkirch, Cedex, C.U. de Strasbourg, France.
Boulay
Anne
A
Masson
Régis
R
Mathelin
Carole
C
Stoll
Isabelle
I
Tomasetto
Catherine
C
Chenard
Marie-Pierre
MP
Gintz
Martine
M
Bellocq
Jean-Pierre
JP
Rio
Marie-Christine
MC
D000818:Animals; D002472:Cell Transformation, Viral / Q000502:physiology*; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000556:secondary; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology*; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic
D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases