Fibroblast activation protein: Pivoting cancer/chemotherapeutic insight towards heart failure

Abstract

An important mechanism for cancer progression is degradation of the extracellular matrix (ECM) which is accompanied by the emergence and proliferation of an activated fibroblast, termed the cancer associated fibroblast (CAF). More specifically, an enzyme pathway identified to be amplified with local cancer progression and proliferation of the CAF, is fibroblast activation protein (FAP). The development and progression of heart failure (HF) irrespective of the etiology is associated with left ventricular (LV) remodeling and changes in ECM structure and function. As with cancer, HF progression is associated with a change in LV myocardial fibroblast growth and function, and expresses a protein signature not dissimilar to the CAF. The overall goal of this review is to put forward the postulate that scientific discoveries regarding FAP in cancer as well as the development of specific chemotherapeutics could be pivoted to target the emergence of FAP in the activated fibroblast subtype and thus hold translationally relevant diagnostic and therapeutic targets in HF.

Keywords: Extracellular matrix; Fibroblast activation; Heart failure.

Fig. 1.

(A) A stylized schematic of FAP based upon structure–function studies[,,,,,,–205]. The extracellular domain containing the 8 bladed propeller imparts substrate specificity whereby the catalytic domain (C) is an amino-acid peptidase which cleaves after a proline residue and is also an endopeptidase which cleaves a glycine-proline sequence. Thus FAP can process ECM proteins directly and also indirectly through activation/deactivation of other proteases and signaling molecules. The function of the intracellular domain remains unclear but may be a target of phosphorylation and thus play a regulatory role. (B) Ribbon diagram for the extracellular domain of FAP which identifies the propeller domains (4 on each side) in grey shading and the catalytic domain in green shading. The arrows indicate the direction where the folded propellers will form a central pore for substrate docking. Reproduced from Aertgeerts, K., Levin, I., Shi, L., Snell, G. P., Jennings, A., Prasad, G. S., Zhang, Y., Kraus, M. L., Salakian, S., Sridhar, V., Wijnands, R., & Tennant, M. G. (2005). Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. The Journal of biological chemistry, 280(20), 19441–19444.

Fig. 2.

Simplified schematic for a potential FAP/TGF amplification loop. TGF is prevented from binding to TGF receptor complexes (denoted as TGF receptor) through sequestration of the latency activation protein (LAP) and latency binding proteins (designated at LTBP). In silico mapping and initial in-vitro studies,[75,76] have identified that FAP can proteolytically disrupt the LAP/LTBP complex which would result in enhanced liberation of TGF. As a consequence, TGF will bind to the TGF-receptor complex and intracellular transduction such as activation of SMADs, such as canonical SMAD3, which has been shown to cause increased FAP transcription.[172] While this is a simplified postulate of a complex proteolytic/signaling interaction, this does put forward an important post-translational event in terms of FAP/TGF and fibroblast activation and ECM remodeling.

Fig. 3.

Myocardial perfusion images using ^99mTc-tetrofosmin at rest, fibroblast activation by ⁶⁸Ga-FAPI PET, scar defined by late gadolinium enhancement (LGE) from cardiac magnetic resonance (CMR), and schematic drawings of LV. Area of fibroblast activation (red) as indicated by ⁶⁸Ga-FAPI-46 PET signal exceeds infarct area (yellow) and distribution of LGE signal within the ante-roseptal wall. HLA = horizontal long axis; SA = short axis; VLA = vertical long axis. This research was originally published in Journal of Nuclear Medicine. Reproduced with permission from Reference [55].

Fig. 4.

Schematic of cardiac fibroblasts proliferating and expressing FAP. These cardiac fibroblasts which emerge with LV remodeling are similar in phenotype to CAFs. Thus, potential therapeutic strategies developed for CAFs could be considered for these cardiac fibroblasts. There are 3 fundamental domains of therapeutics being developed and explored: small molecules such as Talabostat and DPP4 Inhibitors, Antibody conjugate strategies such as immunotoxins, and immunotherapy by which adoptively transferred FAP-specific re-directed T cells are utilized.