Detailed Research on Disseminated Tumor Cells in Bone Marrow of Gastric Cancer Patients: Correlation with Tumor Hypoxia and Clinical Relevance

Larissa Bubnovskaya; Antonina Kovelskaya; Lilya Gumenyuk; Irina Ganusevich; Lesya Mamontova; Victor Mikhailenko; Dmitry Osinsky; Sergej Merentsev; Sergej Osinsky

Larissa Bubnovskaya R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Antonina Kovelskaya R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Lilya Gumenyuk R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Irina Ganusevich R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Lesya Mamontova R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Victor Mikhailenko R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.
Dmitry Osinsky City Clinical Oncological Center, Verchovynna Str.69, Kiev-03115, Ukraine.
Sergej Merentsev City Clinical Oncological Center, Verchovynna Str.69, Kiev-03115, Ukraine.
Sergej Osinsky R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Vasilkovskaya Str. 45, Kiev-03022, Ukraine.

Keywords: Disseminated tumor cells, gastric cancer, tumor hypoxia, hypoxia-associated elements, chemotherapy, overall survival

Abstract

Aim: The evaluation of the clinical relevance of disseminated tumor cells (DTCs) in bone marrow (BM) of patients with gastric cancer (GC) and their association with primary tumor hypoxia.

Methods: It was used immunocytochemistry (detection of DTCs, VEGFR-1 expression in BM); immunohistochemistry (CD68, CD34, VEGF, and VEGFR-1 (Flt-1) expression); NMR spectroscopy (level of tumor hypoxia), zymography (MMP-2 and MMP-9 activity, both in tumor and BM).

Results: DTCs were detected in 51.4% of GC patients with M₀. There was significant correlation between frequency of DTCs in BM and level of tumor hypoxia (P<0.024). DTCs presence was accompanied with Flt-1 positivity of BM. The correlation between DTCs and tumor VEGF expression in patients with M₀ was shown (P<0.0248). Activity of MMP-2 and MMP-9 in BM was linked with DTCs in BM in patients with M₀ (P<0.05). Overall survival (OS) of patients with category M₀ and DTCs in BM was shorter than that of patients without DTCs (P=0.0497). OS of patients with DTCs and Flt-1-positive BM was shorter than that of patients without DTCs but with Flt-1-positive BM (P=0.0437). Conclusion: Appearance of DTCs in BM correlates with hypoxia level in primary tumors. Detection of DTCs in GC patients may be relevant indicator for adjuvant chemotherapy using.