Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize

被引:478
作者
Fukumura, Dai
Jain, Rakesh K.
机构
[1] Massachusetts Gen Hosp, Edwin L Steele Lab Tumor Biol, Dept Radiat Oncol, Boston, MA 02114 USA
[2] Harvard Univ, Sch Med, Boston, MA 02114 USA
关键词
microenvironment; hypoxia; acidosis; interstitial fluid pressure; angiogenesis; microcircualtion; lymphangiogenesis; lymphatic metastasis; stromal cells; vascular endothelial growth factor; intravital microscopy;
D O I
10.1002/jcb.21187
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A solid tumor is an organ-like entity comprised of neoplastic cells and non-transformed host stromal cells embedded in an extracellular matrix. The expression of various genes is influenced by interactions among these cells, surrounding matrix, and their local physical and biochemical microenvironment. The products encoded by these genes, in turn, control the pathophysiological characteristics of the tumor, and give rise to the abnormal organization, structure, and function of tumor blood vessels. These abnormalities contribute to heterogeneous blood flow, vascular permeability, and microenvironment. Proliferating tumor cells produce solid stress which compresses blood and lymphatic vessels. As a result of vessel leakiness and lack of functional lymphatics, interstitial fluid pressure is significantly elevated in solid tumors. Each of these abnormalities forms a physiological barrier to the delivery of therapeutic agents to tumors. Furthermore, the metabolic microenvironment in tumors such as hypoxia and acidosis hinder the efficacy of anti-tumor treatments such as radiation therapy and chemotherapy. A judicious application of anti-angiogenic therapy has the potential to overcome these problems by normalizing the tumor vessels and making them more efficient for delivery of oxygen and drugs. Combined anti-angiogenic and conventional therapies have shown promise in the clinic.
引用
收藏
页码:937 / 949
页数:13
相关论文
共 78 条
[41]  
Jain R.K., 2004, CLIN ONCOLOGY, P153
[42]   Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor [J].
Jain, RK ;
Safabakhsh, N ;
Sckell, A ;
Chen, Y ;
Jiang, P ;
Benjamin, L ;
Yuan, F ;
Keshet, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (18) :10820-10825
[43]   Vessels of death or life [J].
Jain, RK ;
Carmeliet, PF .
SCIENTIFIC AMERICAN, 2001, 285 (06) :38-45
[44]   TRANSPORT OF MOLECULES ACROSS TUMOR VASCULATURE [J].
JAIN, RK .
CANCER AND METASTASIS REVIEWS, 1987, 6 (04) :559-593
[45]   BARRIERS TO DRUG-DELIVERY IN SOLID TUMORS [J].
JAIN, RK .
SCIENTIFIC AMERICAN, 1994, 271 (01) :58-65
[46]   Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy [J].
Jain, RK .
NATURE MEDICINE, 2001, 7 (09) :987-989
[47]   Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy [J].
Jain, RK .
SCIENCE, 2005, 307 (5706) :58-62
[48]  
JAIN RK, 1988, CANCER RES, V48, P2641
[49]  
Kadambi A, 2001, CANCER RES, V61, P2404
[50]  
Krogh A., 1922, ANANTOMY PHYSL CAPIL