Clinical Implications of Fibroblast Activation Protein in Patients with Colon Cancer

Abstract

Purpose: Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty. Experimental Design: Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models. Results: One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in >93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, À0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival. Conclusion: Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

“…Moreover, this marker is upregulated when mesenchymal stem cells are recruited into growing tumors [21,22]. Tumor-associated stromal expression of FAP was found to be associated with more aggressive disease progression, and potential development of metastasis, recurrence, and death in colon and pancreatic cancers [23][24][25]. Previous studies in ovarian cancers treated with standard surgery followed by chemotherapy showed an association of FAP with advanced stage disease, lymph node metastasis, omental involvement, lymphovascular disease, and increased angiogenesis, but there is lack of data on the association of FAP with patient outcomes [26].…”

Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion

“…FAP immunostaining in fibroblasts was evaluated in CRC and in close vicinity to colonic epithelial cells in normal mucosa, hyperplastic polyps, and adenomas. Stromal staining was assessed as negative, ϩ, ϩϩ, or ϩϩϩ, according to the semiquantitative scale suggested by Henry et al 13 The ϩ, ϩϩ and ϩϩϩ categories were considered to be positive for FAP staining. Occasional epithelial staining was not analyzed.…”

“…9 It is normally expressed transiently in healing wounds, and abundantly by activated stromal fibroblasts in CRC and other human epithelial malignancies (breast, lung, and ovary carcinomas). 10 -12 Abundant FAP expression has been implicated as a negative prognostic factor in patients with metastatic CRC, 13 but its biological role is still not clear. However, a clinical trial on CRC patients using talabostat, an inhibitor of FAP-enzymatic activity, showed a minimal clinical effect, and the authors suggest that the partial inhibition may be due to another contributing factor or factors.…”

Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer

“…9 FAP is expressed infrequently on the colon cancer cells themselves, and stromal cells residing in colorectal adenomas are also predominantly FAP negative, suggesting that malignancy is required for effective FAP stromal induction. 10 Given its ubiquitous expression in both primary and metastatic colorectal carcinomas, FAP has been targeted by monoclonal antibodies, 11 but these non-inhibitory antibodies did not show clinical activity.…”

“…17,18 In a phase I trial of Val-boroPro in patients receiving myelosuppressive chemotherapy, the maximum tolerated dose was not reached up to 1200 μg per day, although orthostatic hypotension was observed at 800 μg per day. 19 Given the robust expression of FAP in the colorectal cancer stroma, 9 studies suggesting FAP portends a worse prognosis, 9 and preliminary evidence of Val-boroPro clinical activity in other clinical settings, [20][21][22] we conducted a phase II trial to evaluate the efficacy and safety of Val-boroPro monotherapy in patients with metastatic colorectal cancer.…”