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Abstract
The tumor microenvironment plays an important role equal to the tumor cell population in the progression of cancer. Consisting of stromal fibroblasts, inflammatory cells, components of the vasculature, normal epithelia, and extracellular matrix, the surrounding environment interacts or “cross-talks” with tumor cells through the release of growth factors, cytokines, proteases, and other bioactive molecules. Tumor growth, formation of new vascular networks, evasion of the host immune system, and invasion and metastasis are processes that co-evolve and become finely optimized and regulated within the tumor microenvironment. However, relatively recent reports on three areas of study have come together to add new levels of complexity to the tumor microenvironment. These include ectodomain shedding of proteins, shedding of membrane-derived vesicles, and novel roles for phospholipids. These dynamic changes that take place in the tumor microenvironment provide new avenues for study and for the early detection of cancer, whereas proteomic technologies provide the means to detect these unique proteins and lipids. Here we review the evolving concepts of the tumor microenvironment that, together with advances in proteomic technologies, hold the promise to facilitate the detection of early-stage cancer.
| Abbreviations and Glossary | ||
| ATX | = | autotaxin, identical to the LPA-producing enzyme lysophospholipase D (lysoPLD) |
| CAF | = | carcinogenic-associated fibroblast |
| c-Met | = | product of the proto-oncogene c-met, also known as the hepatocyte growth factor receptor |
| E-Cadherin | = | epithelial cadherin |
| EC | = | endothelial cell |
| ECM | = | extracellular matrix |
| EGF | = | epidermal growth factor |
| EMMPRIN | = | extracellular matrix metalloproteinase inducer |
| EMT | = | epithelial-to-mesenchymal transition |
| EOC | = | epithelial ovarian carcinoma |
| FasL | = | Fas ligand |
| FGF | = | fibroblast growth factor |
| FGFR | = | fibroblast growth factor receptor |
| FSP | = | fibroblast-secreted protein |
| GPCR | = | G-Protein coupled receptor |
| HB-HGF | = | heparin-binding epidermal growth factor-like growth factor |
| HGF | = | hepatocyte growth factor |
| HGF/SF | = | hepatocyte growth factor/scatter factor |
| HRCC | = | human renal carcinoma cells |
| HSPG | = | heparan-sulfate proteoglycan |
| IGF | = | insulin-like growth factor |
| IL | = | interleukin |
| IOSE-29 | = | immortalized ovarian surface epithelial cell line 29 |
| LPA | = | lysophosphatidic acid |
| LPC | = | lysophosphatidylcholine |
| LPS | = | lipopolysaccharide |
| lysoPLD | = | lysophospholipase D |
| MAP | = | mitogen-activated protein |
| MCP | = | monocyte chemoattractant protein |
| MF | = | membrane fragments |
| MMP | = | matrix metalloproteinase |
| MT1-MMP | = | membrane-type 1-matrix metalloproteinase, also known as MMP-14 |
| N-Cadherin | = | neuronal cadherin |
| NK | = | natural killer |
| NO | = | nitric oxide |
| PAF | = | platelet-activating factor |
| PDGF | = | platelet-derived growth factor |
| PKC | = | protein kinase C |
| SPC | = | sphingosylphosphorylcholine |
| S1P | = | sphingosine-1-phosphate |
| Tie-1 | = | and Tie-2 are endothelial-specific receptor tyrosine kinases. Ligands for Tie-1 are not known; however, ligands for Tie-2 include the angiopoietins Ang-1 and Ang-2 |
| TGF | = | transforming growth factor |
| TNF | = | tumor necrosis factor |
| uPA | = | urinary-type plasminogen activator |
| uPAR | = | urinary-type plasminogen activator receptor |
| VEGF | = | vascular endothelial growth factor |
| VEGFR | = | vascular endothelial growth factor receptor |
| Abbreviations and Glossary | ||
| ATX | = | autotaxin, identical to the LPA-producing enzyme lysophospholipase D (lysoPLD) |
| CAF | = | carcinogenic-associated fibroblast |
| c-Met | = | product of the proto-oncogene c-met, also known as the hepatocyte growth factor receptor |
| E-Cadherin | = | epithelial cadherin |
| EC | = | endothelial cell |
| ECM | = | extracellular matrix |
| EGF | = | epidermal growth factor |
| EMMPRIN | = | extracellular matrix metalloproteinase inducer |
| EMT | = | epithelial-to-mesenchymal transition |
| EOC | = | epithelial ovarian carcinoma |
| FasL | = | Fas ligand |
| FGF | = | fibroblast growth factor |
| FGFR | = | fibroblast growth factor receptor |
| FSP | = | fibroblast-secreted protein |
| GPCR | = | G-Protein coupled receptor |
| HB-HGF | = | heparin-binding epidermal growth factor-like growth factor |
| HGF | = | hepatocyte growth factor |
| HGF/SF | = | hepatocyte growth factor/scatter factor |
| HRCC | = | human renal carcinoma cells |
| HSPG | = | heparan-sulfate proteoglycan |
| IGF | = | insulin-like growth factor |
| IL | = | interleukin |
| IOSE-29 | = | immortalized ovarian surface epithelial cell line 29 |
| LPA | = | lysophosphatidic acid |
| LPC | = | lysophosphatidylcholine |
| LPS | = | lipopolysaccharide |
| lysoPLD | = | lysophospholipase D |
| MAP | = | mitogen-activated protein |
| MCP | = | monocyte chemoattractant protein |
| MF | = | membrane fragments |
| MMP | = | matrix metalloproteinase |
| MT1-MMP | = | membrane-type 1-matrix metalloproteinase, also known as MMP-14 |
| N-Cadherin | = | neuronal cadherin |
| NK | = | natural killer |
| NO | = | nitric oxide |
| PAF | = | platelet-activating factor |
| PDGF | = | platelet-derived growth factor |
| PKC | = | protein kinase C |
| SPC | = | sphingosylphosphorylcholine |
| S1P | = | sphingosine-1-phosphate |
| Tie-1 | = | and Tie-2 are endothelial-specific receptor tyrosine kinases. Ligands for Tie-1 are not known; however, ligands for Tie-2 include the angiopoietins Ang-1 and Ang-2 |
| TGF | = | transforming growth factor |
| TNF | = | tumor necrosis factor |
| uPA | = | urinary-type plasminogen activator |
| uPAR | = | urinary-type plasminogen activator receptor |
| VEGF | = | vascular endothelial growth factor |
| VEGFR | = | vascular endothelial growth factor receptor |
Notes
*Editor's note: See Glossary.
*Editor's note: Refers to migration over a substrate-bound gradient, as opposed to “chemotactic” (where the gradient is soluble).