The Beta Subunit of Human Hemoglobin Inhibits Lung and Bone Marrow Metastasis - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Shelly Maman ¹ Orit Sagi-Assif ¹ Weirong Yuan ³ Ravit Ginat ¹ Tsipi Meshel ¹ Inna Zubrilov ¹ Yona Keisari ² Wuyuan Lu ³ Isaac P. Witz ¹

¹The Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel
²The Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Israel
³The Department of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine, USA

Background. Metastatic disease may occur years or even decades after a successful treatment of the cancer patient. This disease progression is due to the propagation of micrometastases to clinically detectable metastasis. We previously showed that soluble factors derived from mouse lungs keep lung micrometastatic cells in check, inhibiting their viability and thus their progression to overt metastasis. Here we isolate and characterize the lung-derived inhibitory factor.

Methods. Reversed-phase HPLC followed by LC-MS/MS isolated and identified the lung-derived inhibitory factor to be the beta subunit of murine hemoglobin (HBB2). Synthesis of 14 peptide segments of 15 amino acids each of the beta subunit of human hemoglobin (HBB) enabled the identification of a short C-terminal region of HBB (designated Metox) as being responsible for the inhibitory activity.

Results. HBB2 and HBB exert growth arrest and apoptosis of human lung-metastasizing tumor cells in-vitro. In-vivo therapy experiments employing Metox which exerts growth arrest and apoptosis of tumor cells in-vitro, inhibits the development of adrenal neuroblastoma tumors in xenografted mice and the development of spontaneous lung and bone marrow metastasis.

Conclusions. In addition to its known functions, the beta subunit of hemoglobin operates as an innate anti-tumor resistance factor restraining the proliferation of cancer cells and keeping them in a state of dormancy. HBB2 is expressed by mouse lung cells and is up-regulated in mice bearing human neuroblastoma micrometastases. HBB may thus be developed into a novel drug and may serve as a biomarker signaling the presence of clinically undetectable micrometastasis.