Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death . Overall, the 5-year survival rate is <10% for stage IV cancer . The cure rate with surgery alone is very low and chemotherapy and radiotherapy are usually needed in patients with untreated metastatic colon cancer. The development of colorectal cancer is characterized by a sequence of events during which normal colonic epithelium gradually transforms to carcinoma tissue, in most cases, via the development of colorectal adenomas . This sequence of events is driven by an accumulation of molecular (epi)genetic alterations causing progressive disorders in cell growth, differentiation and apoptosis [4, 5]. Apoptosis, or programmed cell death, plays an important role in the development and maintenance of tissue homeostasis but also represents an effective mechanism by which abnormal cells, such as tumor cells, can be eliminated [6–8]. Abnormalities in apoptotic function or resistance to apoptosis have been identified as important events in the pathogenesis of colorectal cancer and its resistance to chemotherapeutic drugs and radiotherapy [9, 10].
In recent years, bevacizumab, a novel humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF) has found widespread clinical use as an angiogenesis inhibitor for certain types of metastatic cancers . Treatment with bevacizumab with/without the combination of other chemotherapeutic agents inhibits VEGF receptor activation and vascular permeability, which eventually lead to tumor cell apoptosis [12, 13]. Apoptosis can be induced passively, through the lack of essential survival signals, or actively, through the ligand-induced trimerization of specific death receptors of the tumor necrosis factor (TNF) receptor family, such as Fas, the TNF receptor, or TRAIL (TNF-related apoptosis-inducing ligand) receptor .
TRAIL (APO-2 ligand) is a transmembrane (type II) glycoprotein that also belongs to the TNF superfamily. The extracellular domain of TRAIL is homologous to that of other family members and shows a homotrimeric subunit structure. Like TNF and Fas ligand (FASL), TRAIL also exists physiologically in a biologically active soluble homotrimeric form, serum-soluble TRAIL; sTRAIL . Several recent studies have indicated that sTRAIL is involved in the pathophysiology of different disease states such as cancer, viral infections, autoimmune diseases and inflammation, and defective apoptosis due to its interaction with its ligand preventing signaling for apoptosis may contribute to these diseases [16–21].
Several studies have shown that both the membrane-bound TRAIL and sTRAIL can induce apoptosis in a wide variety of tumor types by activating death receptors [22–24]. sTRAIL is also used as a positive marker for apoptosis . However, it has been observed that the cytotoxic effects of antiangiogenic agents are increased in clinical phase II and III studies when these agents are combined with TRAIL-related therapies [26–28]. Another study with human glioblastoma cells has indicated that TRAIL inhibits angiogenesis stimulated by VEGF expression .
However, recently used RECIST parameters (Response Evaluation Criteria for Solid Tumors; responders vs. non-responders) are not adequate to document the differences in treatment response . Therefore, there is a need for a sensitive, specific and reliable serum marker to monitor the therapeutic response.
The purpose of our study was to evaluate the possible use of sTRAIL as a marker for bevacizumab treatment efficacy at the cell apoptosis-linked step.