Differential Expression of the 18 kDa Translocator Protein (TSPO) by Neoplastic and Inflammatory Cells in Mouse Tumors of Breast Cancer

Abstract

Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The 18 kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), is expressed in activated immune cells such as macrophages, but also in a number of cancer cell lines such as those of breast cancer. There is an increasing clinical interest in TSPO expression as it has been proposed as a poor prognostic factor for survival in lymph-node negative breast cancer patients. This study aims to assess of the presence of neoplastic cell-associated TSPO and tumor macrophage-associated TSPO in mouse xenografts generated from the MDA-MB-231 and the MCF-7 breast cancer cell lines, as well as 25 different breast tumors originally derived from patient-tissue but propagated in mice using two antibodies, each specific to either the human or the murine form of TSPO. Autoradiography with the TSPO ligand [¹⁸F]DPA-714 and immunohistochemistry were also performed on the excised tumor tissues from the MDA-MB-231, MCF-7 and one of the patient-derived xenografts (HBCx-12B). High TSPO expression (either cancer or stromal cell-associated, or both) was measured in 20/25 (80%) of the patient-derived breast cancer xenografts. [¹⁸F]DPA-714 showed displaceable binding to both the human and murine TSPO on tumor tissue sections. Immunohistochemistry demonstrated that a significant portion of the tumor stromal TSPO expression colocalized with F4/80 positive macrophages cells. This study constitutes a first report of the tumor TSPO expression by mixed cell populations, and it may have important implications for cancer biology as well as for the development of imaging and therapeutic ligands targeted to TSPO.

The mitochondrial voltage-dependent anion channel 1 in tumor cells

“…TSPO is a multi-functional protein associated with the regulation of cholesterol transport, steroidogenesis, porphyrin transport, heme synthesis, apoptosis and cell proliferation [340]. TSPO is over-expressed in different types of tumors and cancer cell lines, such as CLL, breast, colorectal, prostate, ovarian, glioma and hepatocarcinoma cancer cells, and its involvement in the modulation of cell proliferation and tumorigenesis has been shown [341,342]. Moreover, increased TSPO expression was correlated with an increased aggressive cancer cell phenotype [341,343].…”

Genetic analysis of dTSPO, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Aβ42‐induced neurodegeneration

“…In addition, TSPO expression is increased in a variety of cancers. Consequently, TSPO ligands have been reported to have therapeutic effects on certain tumors through modulation of cellular proliferation and apoptosis (Furre et al ., 2005; Fafalios et al ., 2009; Zheng et al ., 2011). …”

Mitochondrial VDAC1: Function in Cell Life and Death and a Target for Cancer Therapy

“…TSPO is associated with the regulation of cholesterol transport, the synthesis of steroid hormones, porphyrin transport, heme synthesis, apoptosis and cell proliferation [305]. Several studies have demonstrated high expression levels of TSPO in different types of tumors and cancer cell lines, such as CLL, breast, colorectal, prostate, ovarian, glioma and hepatocarcinoma cells, and have shown its involvement in the modulation of cell proliferation and tumorigenesis [306,307]. Moreover, increased TSPO expression correlated with an increased aggressive cancer cell phenotype [307,308].…”