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. 2023 Oct 13;13(20):3199.
doi: 10.3390/diagnostics13203199.

Tumor Progression from a Fibroblast Activation Protein Perspective: Novel Diagnostic and Therapeutic Scenarios for Colorectal Cancer

Martina Rossetti  1 , Stefano Stanca  1 , Rossella Del Frate  1 , Francesco Bartoli  2 , Andrea Marciano  2 , Enrica Esposito  2 , Alessandra Fantoni  1 , Anna Paola Erba  3 , Piero Vincenzo Lippolis  4 , Pinuccia Faviana  1
Affiliations

Tumor Progression from a Fibroblast Activation Protein Perspective: Novel Diagnostic and Therapeutic Scenarios for Colorectal Cancer

Martina Rossetti et al. Diagnostics (Basel). .

Abstract

In 2020, the Global Cancer Observatory estimated the incidence of colorectal cancer (CRC) at around 10.7% coupled with a mortality rate of 9.5%. The explanation for these values lies in the tumor microenvironment consisting of the extracellular matrix and cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) offers a promising target for cancer therapy since its functions contribute to tumor progression. Immunohistochemistry examination of FAP, fibronectin ED-B, and CXCR4 in primary tumors and their respective synchronous and/or metachronous metastases along with semiquantitative analysis have been carried out on histological samples of 50 patients diagnosed with metastatic CRC. The intensity of FAP, articulated by both "Intensity %" and "Intensity score", is lower in the first metastasis compared to the primary tumor with a statistically significant correlation. No significant correlations have been observed regarding fibronectin ED-B and CXCR4. Tumors that produce FAP have an ambivalent relationship with this protein. At first, they exploit FAP, but later they reduce its expressiveness. Although our study has not directly included FAP-Inhibitor (FAPI) PET/CT, the considerable expression of FAP reveals its potential as a diagnostic and therapeutic tool worthy of further investigation. This dynamic relationship between cancer and FAP has substantial diagnostic and therapeutic implications.

Keywords: CAFs; FAP; colorectal cancer; imaging; radiometabolic therapy; tumor microenvironment.

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Conflict of interest statement

The authors declare the following competing financial interests related to the content of the present work: P.A.E. and F.B. have contract research with Philogen.

Figures

Figure 1
Figure 1
The CRC staging based on the TNM classification.
Figure 2
Figure 2
Cytoplasmic FAP staining involves the stromal CAFs next to the neoplastic cells. CRC primary site (A) and liver metastasis (B) show FAP-positive CAFs demarcating tumor glands (20× magnification). Nuclear CXCR4 is strong and diffuse in both the primary tumor (C) and in liver metastasis (D) (20× magnification).
Figure 3
Figure 3
Distribution of the FAP expression based on the “Intensity score” in the primitive tumor and in the 1st metastasis. FAP is significantly lower in the 1st metastasis compared to the primary tumor.
Figure 4
Figure 4
Distribution of the FAP expression based on the “Intensity %” in the primitive tumor and in the 1st metastasis. FAP is significantly lower in the 1st metastasis compared to the primary tumor.
Figure 5
Figure 5
Distribution of FAP in the subgroups with and without KRAS mutation. FAP shows higher values in both the primary tumor and the 1st metastasis in patients with KRAS mutation compared to those without mutations; nevertheless, the results are not statistically significant (p value = 0.39).
Figure 6
Figure 6
Distribution of FAP in 1st metastasis in the subgroups with and without KRAS mutation. FAP shows higher values in both the primary tumor and the 1st metastasis in patients with KRAS mutation compared to those without mutations; nevertheless, the results are not statistically significant (p value = 0.26).
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