Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug.
Increasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1(+/+) versus Cav-1(-/-) age-matched young female mice). Mammary tumors grown in a Cav-1-deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging). Mammary tumors grown in a Cav-1-deficient tumor microenvironment were more than fivefold larger than tumors grown in a wild-type microenvironment. Thus, a Cav-1-deficient tumor microenvironment provides a fertile soil for breast cancer tumor growth. Interestingly, the mammary tumor-promoting effects of a Cav-1-deficient microenvironment were estrogen and progesterone independent. In this context, chemoprevention was achieved by using the mammalian target of rapamycin (mTOR) inhibitor and anti-aging drug, rapamycin. Systemic rapamycin treatment of mammary tumors grown in a Cav-1-deficient microenvironment significantly inhibited their tumor growth, decreased their stromal content, and reduced the levels of both vimentin and phospho-S6 in Cav-1-deficient cancer-associated fibroblasts. Since stromal loss of Cav-1 is a marker of a lethal tumor microenvironment in breast tumors, these high-risk patients might benefit from treatment with mTOR inhibitors, such as rapamycin or other rapamycin-related compounds (rapalogues).
Department of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. isabelle.mercier@jefferson.edu
Isabelle
I
Mercier
Jeanette
J
Camacho
Kanani
K
Titchen
Donna M
DM
Gonzales
Kevin
K
Quann
Kelly G
KG
Bryant
Alexander
A
Molchansky
Janet N
JN
Milliman
Diana
D
Whitaker-Menezes
Federica
F
Sotgia
Jean-François
JF
Jasmin
Roland
R
Schwarting
Richard G
RG
Pestell
Mikhail V
MV
Blagosklonny
Michael P
MP
Lisanti
D000375:Aging / Q000502:physiology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D051242:Caveolin 1 / Q000172:deficiency / Q000502:physiology*; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010052:Ovariectomy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use*; D017154:Stromal Cells / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D051242:Caveolin 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus