Cancer ego-system in glioma: an iron-replenishing niche network systemically self-organized by cancer stem cells

Abstract

For all living organisms, the adaptation to outside environments is an essential determinant to survive natural and artificial selections and to sustain the whole ecosystem intact with functional biodiversity. Likewise, cancer cells have similar characteristics that evade not only stresses from the host-internal innate and adaptive immune systems but also those from host-externally administered therapeutic interventions. Such selfish characteristics of cancer cells lead to the formation of cancerous ecosystem with a wide variety of phenotypic heterogeneity, which should be called cancer "egosystem" from the host point of view. Recently increasing evidence demonstrates that cancer stem cells (CSCs) are responsible for this cancer egosystem by effectively exploiting host inflammatory and hematopoietic cells and thereby reconstructing their own advantageous niches, which may well be a driving force in cancer recurrence. CSCs are further likely to render multiple niches mutually interconnected and cooperating as a network to support back CSCs themselves. Here, we summarize a recently identified iron-replenishing niche network self-organized by glioma CSCs (GSCs) through remote regulation of host myeloid and erythroid lineage cells. GSCs recruit bone marrow (BM)-derived inflammatory monocytes into tumor parenchyma, facilitate their differentiation into macrophages (Mφs) and skew their polarization into pro-tumoral phenotype, i.e., tumor-associated Mφs (TAMs). Meanwhile, GSCs distantly enhance erythropoiesis in host hematopoietic organs like BM and spleen potentially by secreting some soluble mediators that maintain continuous supply of erythrocytes within tumors. In addition, as normal red pulp Mφs (RPMs) under steady state conditions in spleen recycle iron by phagocytosing the aged or damaged erythrocytes (a/dECs) and release it in time of need, TAMs at least in gliomas phagocytose the hemorrhaged erythrocytes within tumors and potentially serve as a source of iron, an important nutrient indispensable to GSC survival and glioma progression. Taken together, these studies provide the substantial evidence that CSCs have a unique strategy to orchestrate multiple niches as an ecosystem that threatens the host living, which in this sense must be an egosystem. Targeting such an adaptive subpopulation of CSCs could achieve drastic disturbance of the CSC niches and subsequent extinction of malignant neoplasms.

Keywords: Cancer ecosystem; Cancer stem cell; Erythrophagocytosis; Erythropoiesis; Glioma; Iron; Niche; Tumor-associated macrophage.

Fig. 1

Systemic cancer ecosystem self-organized by CSCs in glioma-bearing mice. A functional niche network for CSCs to replenish iron, indispensable to GSC expansion themselves, is delineated by interconnecting GSC-induced TAM development in brain, and GSC-triggered enhanced erythropoiesis in peripheral. (1) Glioma: TfR⁺ GSCs recruit CCR2⁺ CD68⁺ inflammatory monocytes (iMo) from peripheral BM and induce F4/80⁺ CD163⁺ CD204⁺ tumor-associated macrophages (TAMs) through secreting some soluble factors such as CCL2 and CSF1/2 [Mo/Mφ development]. On the other hand, GSCs facilitate medullar and extramedullar erythropoiesis in peripheral hematopoietic organs, i.e., BM and spleen, potentially through secreting some soluble mediators. Collectively, Ter119⁺ hemorrhaged erythrocytes (hEC) infiltrating from peripheral are phagocytosed by the TAMs in brain and catabolized into iron [erythrophagocytosis and iron recycling]. Iron is stored in TAMs and potentially released upon the demands of GSCs highly expressing the receptor for the iron-carrier transferrin (Tf) [iron replenishment]. (2) Spleen: CD163⁺ TIM4⁺ red pulp macrophages (RPMs) originally have the ability to engulf the aged and damaged erythrocytes (a/dECs) externalizing phosphatidylserine (PS) at the cell surface to recycle and release iron into blood stream at the time of needs [erythrophagocytosis and iron recycling]. (3) Bone marrow (BM): hematopoietic differentiation from common myeloid progenitors (cMP) to erythroblasts (EB), reticulocytes (Retic), and erythrocytes (EC) is enhanced in glioma-bearing mouse BM [erythropoiesis], potentially maintaining the influx of erythrocytes hemorrhaged into glioma tissues. In BM erythropoiesis, CD169⁺ nurse macrophages uptake the recycling iron from blood stream and supply it for EBs to synthesize hemoglobin from heme composed of protoporphyrin IX (PpIX) and iron. Such heme synthesis pathway is also elevated in iron-demanding TfR⁺ GSCs, causing them to escape from 5-ALA-based photodynamic diagnosis (PDD) during surgical operation