Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer

Abstract

We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.

Myeloid-Derived Suppressor Cells as Therapeutic Targets in Uterine Cervical and Endometrial Cancers

“…Consistent with the findings of in vitro and in vivo experiments, an increase in the number of circulating or tumor-infiltrating MDSCs was associated with a decrease in the number of tumor-infiltrating CD8 + T cells [ 29 , 31 , 35 ]. An increased number of MDSCs was also associated with unfavorable clinicopathological parameters, including advanced clinical stage [ 35 ], visceral or lymph node metastases [ 22 , 35 , 38 ], deep stromal invasion [ 35 ], poor sensitivity to anticancer treatments (radiotherapy or chemotherapy) [ 21 , 28 , 29 ], high recurrence rate [ 35 ], and short survival [ 21 , 28 , 29 , 31 ] in patients with uterine cervical and endometrial cancers ( Table 2 ). Moreover, it has been recently demonstrated that MDSC-mediated premetastatic niche formation in the lymph nodes induces 18F-fluorodeoxyglucose (FDG) uptake during FDG-positron emission tomography/computed tomography and causes false-positive detection of nodal metastasis [ 23 ].…”

“…Further, a co-culture experiment indicated that MDSCs in patients with cervical cancer can be induced by tumor-derived factors [ 27 ]. Factors that induced MDSC in mice models of uterine endometrial and cervical cancer include tumor-derived G-CSF, IL-6, estradiol (E2), and Swainsonine [ 21 , 22 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. MDSCs obtained from these experimental models have been shown to inhibit the activity of CD8 + T cells [ 21 , 22 , 28 , 29 , 30 , 31 , 35 ], stimulate tumor angiogenesis [ 21 ], contribute to premetastatic niche formation [ 22 , 23 ], and increase the stem-like properties of cancer cells [ 29 , 30 ], all of which can promote tumor progression by facilitating tumor growth, metastasis [ 22 ], and resistance to anticancer treatments, including chemotherapy and radiotherapy [ 21 , 28 ].…”

“…In 2014, Mabuchi et al [ 21 ] and Vanderstraeten et al [ 36 ] first demonstrated an increased number of MDSCs in patients with cervical and endometrial cancers, respectively ( Table 2 ). Since then, an increasing number of reports have suggested that the number of M–MDSCs and PMN–MDSCs is significantly increased in peripheral blood mononuclear cells (PBMCs) [ 21 , 22 , 28 , 35 , 37 ], lymph nodes [ 23 , 38 ], and tumors [ 29 , 30 , 31 , 33 , 36 , 39 ] in patients with uterine cervical and endometrial cancers. The ratio of PMN–MDSCs and M–MDSCs is unknown in cervical cancer; however, a previous study has suggested that G–MDSCs are the dominant subset in endometrial cancer [ 36 ].…”

“…Various MDSC-targeting strategies have been evaluated in murine models of uterine cervical and endometrial cancers ( Table 2 ), such as anti-Gr-1 antibody [ 22 , 29 , 31 ], anti-IL-6 antibody [ 32 ], COX-2 inhibitor [ 29 ], STAT3 inhibition [ 32 ], and splenectomy [ 21 , 28 ]. They demonstrated significant activity in reducing the number of MDSCs from the TME or inhibiting their suppressive activity against CD8 + T cells, which leads to the inhibition of tumor growth or metastasis [ 21 , 22 , 29 , 33 ], prolongation of survival [ 31 ], attenuation of the growth-promoting effect of E2 [ 33 ], or enhancement of the efficacies of existing anticancer treatments, including cisplatin therapy [ 28 ] or radiotherapy [ 21 ]. In addition to the inhibition of the immunosuppressive activity of MDSCs, depletion of MDSCs has been shown to successfully attenuate premetastatic niche formation and inhibit visceral organ metastasis in uterine cervical and endometrial cancers [ 22 ].…”

“…Moreover, recently, it was found that an increased number of MDSCs was associated with increased bone marrow FDG uptake in patients with uterine cervical cancer [ 31 ]. Thus, by evaluating bone marrow FDG uptake, we might be able to identify a group of patients with increased MDSC who are candidates for MDSC-targeting agents.…”