Abstract
In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and
experimental studies have shown its provoking role on tumor growth and metastasis.
However, investigations have shown that HB chains presented by tumor vascular pericytes
or serum protein complexes of HB could also induce antitumor immunity, which may be
harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows
that expression of HBs is not restricted to erythrocytes and that HBs exist in the
cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous
system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and
tumor cells, and they are increased in certain tumors including breast, lung, colon,
and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid
of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with
posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain
peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative
and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis
via influencing hemorphins and perturbing regulations of immune surveillance and cell
growth in the neuroectodermal tissues. The β-globin gene cluster resides in the chromosome
region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject
to epigenetic regulation. Thus the β-globin loci may exert haplotypal interactions
with these. Some clues support this theory. It is well established that iron load
induces liver cancer in thalassemia major; however iron load–independent associations
also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore,
association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates
in the thalassemia trait. In the African Herero population, a mutant form of δ-globin
is very prevalent, and this population has higher rates of pediatric brain tumors.
Globins are also expressed in healthy endothelia and in tumoral vessels, indicating
potential involvement in angiogenesis. Studies on HBs and their cleavage peptides
in cancers and brain tumors may lead to innovative treatment strategies.
Keywords
hemoglobins - brain tumors - 11p15.5 gene cluster
