Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis.
Recent improvements in diagnostic methods have opened avenues for detection and treatment of (pre)malignant lesions at early stages. However, due to the lack of spontaneous tumor models that both mimic human carcinogenesis and allow direct optical imaging of the vasculature, little is known about the function of blood and lymphatic vessels during the early stages of cancer development. Here, we used a spontaneous carcinogenesis model in the skin of DNA polymerase eta-deficient mice and found that interstitial fluid pressure was already elevated in the hyperplastic/dysplastic stage. This was accompanied by angiogenic blood vasculature that exhibited altered permeability, vessel compression, and decreased alpha-smooth muscle actin-positive perivascular cell coverage. In addition, the lymphatic vessels in hyperplastic/dysplastic lesions were partly compressed and nonfunctional. These novel insights may aid early detection and treatment strategies for cancer.
Hagendoorn
Jeroen
J
Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA.
Tong
Ricky
R
Fukumura
Dai
D
Lin
Qingcong
Q
Lobo
Jennifer
J
Padera
Timothy P
TP
Xu
Lei
L
Kucherlapati
Raju
R
Jain
Rakesh K
RK
D000818:Animals; D001808:Blood Vessels / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency; D045604:Extracellular Fluid / Q000502:physiology*; D006874:Hydrostatic Pressure; D006965:Hyperplasia; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000098:blood supply* / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply* / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
D004259:DNA-Directed DNA Polymerase; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases