Molecular imaging of integrin αvβ6 expression in living subjects

Abstract

Integrins, a family of cell adhesion molecules composed of α and β heterodimeric subunits, are involved in a wide range of cell-extracellular matrix and cell-cell interactions. The study of integrin family members as targets for molecular imaging and therapy has been generally limited with the exception of integrin αvβ3. vβ6, a member of the integrin family, is expressed at low or undetectable levels in normal tissues, but is widely upregulated during many pathological and physiological processes, especially cancer and fibrosis, making it a promising target for molecular imaging. Noninvasive and quantitative imaging of integrin vβ6 expression would be very useful for disease diagnosis, treatment monitoring, and prognosis assessment. Although various molecular probes have been developed for positron emission tomography and single-photon emission computed tomography imaging of integrin vβ6 expression in preclinical animal models, further research efforts are required to optimize integrin vβ6-targeting probes for future potential clinical applications in the fields of oncology and beyond.

Keywords: Molecular probe; cancer; fibrosis; noninvasive imaging; positron emission tomography (PET); single-photon emission computed tomography (SPECT); wound healing.

Figure 1

The integrin family in humans: 18 α and 8 β subunits assemble into 24 different functional heterodimers.

Figure 2

Small-animal PET imaging of integrin α_vβ₆ expression in cancer. A: Representative transaxial PET images of [¹⁸F]FBA-A20FMDV2 and [¹⁸F]FDG in the same mouse with the positive (α_vβ₆-expressing DX3puroβ₆) tumors located near the left shoulder and the negative (control DX3puro) tumors near the right shoulder. Adapted with permission from the American Association for Cancer Research: ref. [50]. B: The photograph and PET image of a mouse bearing both BxPC-3 α_vβ₆-positive (T+) and α_vβ₆-negative 293 (T-) xenografts injected with ⁶⁴Cu-DOTA-S₀2. Adapted with permission from the American Association for Cancer Research: ref. [59].

Figure 3

Small-animal SPECT imaging of integrin α_vβ₆ expression in cancer. (A) Small-animal SPECT (left) and SPECT/CT (right) images of mice bearing α_vβ₆-negative A375Ppuro (left shoulder) and α_vβ₆-positive A375Pβ₆ (right shoulder) tumors with ¹¹¹In-DTPA-A20FMDV2. Adapted with permission from ref. [71]. Copyright (2010) Pathological Society of Great Britain and Ireland. (B) Coronal SPECT/CT images of a mouse bearing α_vβ₆-positive HCC4006 xenograft (left) and a mouse bearing α_vβ₆-negative H838 xenograft (right) after injection of ^99mTc-SAAC-S₀2. Adapted with permission from ref. [74]. Copyright (2014) American Chemical Society. (C) Whole-body posterior and right lateral SPECT/CT images of nude mice with liver metastasis of α_vβ₆-positive BxPC-3 tumors after ^99mTc-HHK injection. (D) Mouse from (C) was sacrificed, and the liver metastasis was verified. This research was originally published in ref. [75]. Copyright (2014) the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figure 4

SPECT imaging of fibrosis. (A) SPECT images of rat with or without liver fibrosis after injection of an integrin α_vβ₃-targeting probe ^99mTc-cRGD. Adapted with permission from ref. [76]. Copyright (2011) American Association for the Study of Liver Diseases. (B, C) Transaxial small-animal SPECT/CT images of ¹¹¹In-DTPA-A20FMDV2 in normal (B) and fibrotic (C) lungs of the mice. (D, E) Transaxial small-animal SPECT/CT images of ¹¹¹In-DTPA-A20FMDV2 in fibrotic lungs of the mice receiving integrin α_vβ₆-blocking antibody (D) or IgG isotype control (E). This research was originally published in ref. [78]. Copyright (2013) the Society of Nuclear Medicine and Molecular Imaging, Inc.