Murine studies have shown that immunological targeting of fibroblast activation protein (FAP) can elicit protective immunity in the absence of significant pathology. Fibroblast activation protein is a product overexpressed by tumor-associated fibroblasts (TAF) and is the predominant component of the stoma in most types of cancer. Tumor-associated fibroblasts differ from normal adult tissue fibroblasts, and instead resemble transient fetal and wound healing-associated fibroblasts. Tumor-associated fibroblasts are critical regulators of tumorigenesis, but differ from tumor cells by being more genetically stable. Therefore, in comparison to tumor cells, TAF may represent more viable therapeutic targets for cancer immunotherapy. To specifically target TAF, we constructed a DNA vaccine directed against FAP. This vaccine significantly suppressed primary tumor and pulmonary metastases primarily through CD8 + T-cell-mediated killing in tumor-bearing mice. Most importantly, tumor-bearing mice vaccinated against FAP exhibited a 1.5-fold increase in lifespan and no significant pathology. These results suggest that FAP, a product preferentially expressed by TAF, could function as an effective tumor rejection antigen. (Cancer Sci 2010; 101: 2325-2332 T he long-term benefits of immunotherapy in cancer patients are threatened by the escape of tumor cells from the immune system due to the inherent genetic instability of tumor cells.(1) For example, mutations in tumor-specific antigens and downregulation of MHC class I antigen can lead to escape from immune surveillance.(2-4) Additionally, defects in apoptotic signaling pathways or upregulation of apoptosis inhibitors can confer resistance to T-cell-mediated killing.(5) Therefore, to increase the efficacy of cancer immunotherapy, targeting of more genetically stable cells in the tumor stroma may prove beneficial.(5-7)The crucial role of the tumor stroma in tumorigenesis and invasion is becoming more widely recognized.(8-10) Early studies revealed that stromal cells can stimulate the transformation of normal epithelial cells and can produce growth factors, cytokines and chemokines that induce the selection and expansion of neoplastic cells. (8,9) In support of this role, tumor cells inoculated in suspension are less tumorigenic than fragments of solid tumors containing the stroma.(11) Importantly, recent reports have suggested that modulation of tumor-stromal fibroblasts (12) or disturbance of the tumor-stromal network can lead to tumor rejection. (13,14) Tumor-associated macrophages and fibroblasts appear to contribute to the local immunosuppressive microenvironment. (15)(16)(17)(18) Tumor-associated fibroblasts (TAF) synthesize both collagen type I and fibroblast activation protein (FAP), a type II membrane-bound serine protease that exhibits dipeptidyl peptidase and collagenase activities implicated in extracellular matrix remodeling. (7,19,20) Some reports have indicated that overexpression of FAP leads to promotion of tumor growth.Consistently, high levels of stromal FAP ha...

Tumor aerobic glycolysis, or the Warburg effect, plays important roles in tumor survival, growth, and metastasis. Pyruvate kinase isoenzyme M2 (PKM2) is a key enzyme that regulates aerobic glycolysis in tumor cells. Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and, in particular, as a potential target for cancer therapy. We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro. We observed that the shRNA can significantly downregulate the expression level of PKM2. The decrease of PKM2 resulted in a decrease in ATP synthesis, which caused intracellular accumulation of docetaxel. Furthermore, the combination of pshRNA-pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro. Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy. In particular, the targeting of PKM2 could, to some extent, be a new way of reversing chemotherapy resistance to cancer therapy. (Cancer Sci 2010; 101: 1447-1453 T umor glycolysis is different from that in many normal adult organizations in metabolism; and the tumor glycolysis plays an important role in tumor energy metabolism.(1,2) Cancer cells take up glucose at higher rates than normal tissue but are prone to produce energy through glycolysis, rather than through mitochondrial oxidation of pyruvate, even when the supply of oxygen is not limited. This effect, called aerobic glycolysis or the Warburg effect, is very important to tumor growth. In addition to providing a rapid rate of ATP production, glycolysis increases lactate production resulting in an acidification of the extracellular milieu, which is believed to facilitate cell invasion and metastasis and bestow a resistance to chemotherapy.(3-5) A high level of glycolysis will also provide an increased supply of the precursors needed for the synthesis of nucleotides, proteins, and lipids in tumor cells. Cancer cells generally show signs of increased glycolysis for ATP generation, due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Increasing evidence has shown that inhibition of glycolysis signaling is a promising approach for cancer treatment. (3,(6)(7)(8)(9)(10) Previous studies have shown that glycolytic genes comprise some of the most unregulated genes in cancer. (11,12) Among them, pyruvate kinase (PK) plays a crucial role in regulating the ratelimiting final step of glycolysis, catalyzing the formation of pyruvate and ATP from phosphoenolpyruvate and ADP. (13,14) Four isoforms of PK have been found in mammals, designated L, R, M1, and M2. Each is differentially expressed in different cell types. (14) The pyruvate kinase M2 isoenzyme (PKM2) is expressed in several differentiated tissues, for example, lung, fat tissue, pancreatic islets, and especially tumor cells.(15-18) During multistep carcinogenesis, the first step is the loss of the tissue-sp...

Esophageal cancer is a highly aggressive malignancy with very poor overall prognosis. Given the strong clinical relevance of SATB1 in esophagus cancer and other cancers suggested by previous studies, the exact function of SATB1 in esophagus cancer development is still unknown. Here we showed that the knockdown of SATB1 in esophageal cancer cell lines diminished the cell proliferation, survival and invasion. Whole genome transcriptome analysis of SATB1 knockdown cells revealed the different gene expression profiles between TE-1 cells and MDA-MB-231 cells. Network analysis and functional experiments further identified FN1 and PDGFRB to be key downstream genes regulated by SATB1 in esophageal cancer cells. Importantly, FN1 and PDGFRB were found to be highly expressed in human esophageal cancer. In summary, we provided the first molecular evidence that SATB1 played an oncogenic role in esophageal cancer by up-regulation of FN1 and PDGFRB.

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