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Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug
- Source :
- Journal of the National Cancer Institute. 104(17)
- Publication Year :
- 2012
-
Abstract
- The tumor stroma constitutes a substantial portion of the mass of many malignancies, including more than 90% of cancers characterized by a desmoplastic reaction (1–3). Tumor cells depend upon the stroma for growth and survival signals, in addition to the nutritional support necessary for tumor maintenance and expansion. When associated with a transformed epithelium, the tumor stroma becomes “activated” (4). Fibroblasts, in particular, consistently undergo changes in morphology and expression profiles when present in the tumor microenvironment (5). These carcinoma-associated fibroblasts (CAFs) produce growth factors that promote tumor growth, angiogenesis, and the recruitment of protumorigenic inflammatory cells (6,7). CAFs can also affect the sensitivity of malignant cells to chemotherapy or radiotherapy (8,9). Furthermore, fibroblast activation protein-alpha (FAP)-positive cells within the stroma may also alter the antitumor immune response (10). Additionally, CAFs alter the extracellular matrix through the production of proteases such as FAP (11–13). FAP is a type II integral membrane serine protease of the dipeptidyl peptidase IV family, which is characterized by post-prolyl cleavage specificity (14,15). However, FAP is unique in this family of enzymes because, in addition to its dipeptidase activity, it also possesses a collagen type I-restricted gelatinase activity (11,16–18). FAP is selectively expressed on the plasma membrane of reactive fibroblasts and pericytes, in the stroma surrounding most epithelial cancers with minimal to no expression by malignant epithelial cells (12,19–21). These FAP-expressing cells may represent or be derived from mesenchymal stem cells that have trafficked to the tumor from bone marrow or other sites (22). Although FAP-positive cells are also observed during wound healing, embryogenesis, and in areas of chronic inflammation and fibrosis (23–26); normal, healthy adult tissues have almost no detectable FAP expression (12,19–21). We developed a therapeutic strategy that exploits FAP’s relative tumor-restricted expression and unique proteolytic activity to activate a peptide-based cytotoxic prodrug within the tumor microenvironment. This approach specifically targets the FAP-expressing CAFs. However, prodrug activation in the extracellular space could also result in the death of non-FAP expressing cell types, such as endothelial cells, due to a bystander effect. Directing therapy at FAP-expressing CAFs within the reactive stroma offers the advantages of providing a more genetically stable target (27) and represents a potential pantumor therapeutic approach because of the common microenvironmental alterations that occur in many different solid tumors (11,28). Here we report the generation of FAP-activated prodrugs that have been characterized for in vitro and in vivo antitumor activity against human breast and prostate cancer models.
- Subjects :
- Male
Cancer Research
Pathology
medicine.medical_specialty
Cell type
Angiogenesis
Transplantation, Heterologous
Antineoplastic Agents
Apoptosis
Breast Neoplasms
Biology
Article
Extracellular matrix
Mice
Fibroblast activation protein, alpha
Stroma
Cell Line, Tumor
Neoplasms
Endopeptidases
medicine
Biomarkers, Tumor
Animals
Humans
Prodrugs
Amino Acids
Fibroblast
Tumor microenvironment
Mice, Inbred BALB C
Serine Endopeptidases
Membrane Proteins
Prostatic Neoplasms
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Oncology
Urinary Bladder Neoplasms
Gelatinases
Cancer research
Thapsigargin
Calcium
Female
Wound healing
Subjects
Details
- ISSN :
- 14602105
- Volume :
- 104
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of the National Cancer Institute
- Accession number :
- edsair.doi.dedup.....da2da545e8eff1006dc566d5ad6df949