Altered expression of fibroblast activation protein-α (FAP) in colorectal adenoma-carcinoma sequence and in lymph node and liver metastases

Abstract

Colorectal cancer (CRC) is a major health problem in elderly people because of its high incidence and high mortality rate. Despite early screening programs, more than half of CRC patients are diagnosed at advanced stages. Fibroblast activation protein-α (FAP) expression in cancer-associated fibroblasts (CAFs) has been associated with a higher risk of metastases and poor survival. Here, we have analyzed the immunohistochemical expression of FAP in 41 adenoma-carcinoma sequences. In addition, FAP expression was analyzed individually and in combination with β-catenin (BCAT), CD44 and Cyclin-D1 expression in primary tumors and in their corresponding lymph node and liver metastases (n=294). Finally, soluble FAP (sFAP) levels in plasma from CRC patients (n=127) were also analyzed by ELISA. FAP was expressed only in CRC tissue and its expression level was found to be higher in tumors exhibiting deeper local invasion and poorer cancer cell differentiation. FAP and concomitant nuclear BCAT expression in cancer cells at the infiltrating front of primary tumors and in lymph node metastases was independently associated with 5- and 10-year cancer specific and disease-free survival. Moreover, lower sFAP levels correlated with poorer survival. These findings support the potential importance of FAP as a biomarker of CRC development and progression.

Altered Tissue and Plasma Levels of Fibroblast Activation Protein-α (FAP) in Renal Tumours

“…Similar paradoxically reduced levels of sFAP have been reported in various studies to be associated with the cancer state and worse survival of patients [ 17 , 20 , 28 ]. Thus, it should be considered that sFAP may not be produced by the tumour tissues.…”

“…This serine peptidase is involved in several phenomena that enable cancer cells to reach invasive properties [ 26 ]. The increased expression of FAP at the invasive front of tumours may contribute to this invasive behaviour [ 20 , 27 ]. The relationship between FAP expression and poor clinical outcome of cancer patients is quite well known [ 19 ].…”

“…However, these data already highlight a contribution to the controversial debate regarding the origin of the soluble isoform of FAP and its variations in the plasma of cancer patients [ 17 , 18 , 20 , 28 ]. Thus, FAP is highly expressed in fibroblasts found in chronic inflammation and fibrotic lesions, as well as in cancer tissues [ 19 , 29 ].…”

“…Indeed, other physiological sources of sFAP have recently been reported including skeletal muscle, liver, and bone marrow [ 18 ]. Thus, it is conceivable that lower sFAP levels in pathological conditions may be indicative of a systemic reaction to a developing tumour [ 17 , 18 , 20 , 28 ]. Another possible pathophysiological mechanism related to decreases of sFAP levels could be associated to the characteristic weight loss of RCC patients with metastatic status [ 30 ].…”

“…Thus, it has been proposed very recently as the next “billion dollar” nuclear theranostic target [ 14 ]. First analyses in liquid biopsies have also demonstrated a prognostic potential for soluble FAP (sFAP) in several solid tumours [ 17 , 18 , 20 ].…”