Page 33 - 2019_10 resto del Mondo_web

The hematologic tumor microenvironment
ating cells in different organs. A paradigm-shifting concept over the past few years is that blood vessels not only deliver nutrients and oxygen to organs and tissues, but that they also sustain stem cells and cancer cells through an 'angiocrine’ mechanism. Consequently, maladapted tumor- associated vascular endothelial cells may confer stem cell- like activity to indolent tumor cells. One example of this is the conversion of dormant lymphoma cells into aggressive lymphoma through the interaction with endothelial cells. This effect is dependent on Notch signaling, since Jagged1 abrogation in endothelial cells can slow down lymphoma progression.2 Another example is the abnormal activation of the fibroblast growth factor receptor 1 (FGFR1)-ETS2 pathway in tumor-associated-vascular endothelial cells dur- ing chemotherapy. Specifically, tumor-derived FGF4 acti- vates FGFR1 in endothelial cells and induces the expression of the transcription factor ETS2. Chemotherapy inhibits the tumor-suppressive checkpoint function of insulin growth factor binding protein 7 (IGFBP7)/angiomodulin and increases the expression of insulin growth factor 1 (IGF1) in endothelial cells, causing an FGFR1-ETS2 feedforward loop which renders naïve IGFR1+ cancer cells resistant to chemotherapy.3 This research helped to show that the FGF4-FGFR1-ETS2 pathway plays a crucial role in tumor- associated endothelium.
Angiocrine signals regulate quiescence and therapy resistance in bone
Kusumbe and colleagues characterized different vessel subtypes comprising endothelial and sub- endothelial/perivascular cells in murine bone marrow. Type H endothelium (named so because of its high expression of endomucin) nurtures bone-forming cells during develop- ment.4 However, alterations of the vascular microenviron- ment can affect the fate of disseminated tumor cells.5 Dormant tumor cells can be awakened through the produc- tion of factors such as periostin (POSTN) and transforming growth factor β-1 (TGFβ-1). Importantly, proximity to the sprouting vasculature supports cancer cell proliferation, whereas a stable vasculature keeps cancer cells dormant. In relation to this, vascular remodeling during aging might alter hematopoiesis. For instance, type H endothelium and its associated osteoprogenitor cells are reduced during aging, possibly affecting hematopoiesis. Consistent with these results, reactivation of endothelial Notch signaling can activate HSC in aged mice, although it cannot fully restore HSC self-renewal.6 Age-associated vascular remod- eling might facilitate the development of myeloid malig- nancies since it promotes myeloid cell expansion.7
The hematopoietic stem cell niche in aging
In this regard, Geiger et al. uncovered several microenvi- ronmental contributions to HSC aging. It had been previ- ously reported that aged stromal cells secrete more pro- inflammatory CC-chemokine ligand 5 (CCL5 or RANTES) but less osteopontin (OPN); these stromal changes imprint some aging-associated phenotypes in HSC.8 Specifically, a decreased frequency of endosteal stromal cells and osteoblasts reduces OPN expression, which is associated with HSC aging (manifested as myeloid skewing). The bone marrow microenvironment of adult OPN knockout mice partly resembles an aged wildtype microenvironment in its increased number of HSC which exhibit reduced engraftment and polarity. However, treatment with OPN fraction D can attenuate the dysfunction of aged long-term
HSC (LT-HSC) and ameliorates HSC by activating integrin α9β1 in HSC.9 Additionally, aged endothelial cells drive hematopoietic aging phenotypes in young HSC, whereas infusion of young endothelial cells enhances endogenous HSC activity in aged mice.10
Metabolism in the tumor microenvironment
Intense efforts are currently being expended to elucidate how cancer cells reshape their malignant microenviron- ment to increase their metabolic fitness and chemoresis- tance.
Subversion of systemic glucose metabolism
as a mechanism to support the growth of leukemic cells
Work by Dr. Ye and colleagues in Dr. Jordan’s laboratory has revealed how leukemic cells subvert the metabolism of systemic glucose for their proliferation. Insulin resistance, besides playing a key role in obesity and diabetes, may facilitate leukemogenesis: leukemic cells can actively reduce glucose utilization by normal tissues to increase their glu- cose bioavailability.11 Collectively, the findings suggest that leukemic cells increase IGFBP1 production from adipose tis- sue, which can cause insulin resistance. An intricate com- munication with the gut causes loss of active glucagon-like peptide-1 (GLP1) and serotonin, which suppresses insulin secretion. Overall, these systemic perturbations are believed to cause desensitization of normal tissues to glu- cose, suggesting a novel therapeutic window based on the restoration of normal glucose regulation.
Mitochondrial trafficking in the tumor microenvironment
Mitochondria are emerging components in the molecular exchange between leukemic cells and their microenviron- ment. The ability of bone marrow mesenchymal stromal cells (BMSC) to donate mitochondria to different cell types12 has emerged as a potentially important process in hemato- logic diseases. Mitochondrial transfer has recently been appreciated to be a previously unrecognized mechanism of intercellular communication associated with chemoresis- tance.13,14 Tunneling nanotubules appear to be the primary mitochondrial exchange route used in acute myeloid leukemia (AML).14 Work from Dr. Rushworth’s laboratory indicates that NADPH oxidase 2 (NOX2)-derived reactive oxygen species, induced by H2O2 or daunorubicin, may enhance mitochondrial transfer from BMSC to AML blasts. The transferred mitochondria appear functionally active and capable of boosting metabolic activity in AML cells.13 A sim- ilar process has been reported in multiple myeloma. Increased oxidative phosphorylation (OXPHOS) in multiple myeloma cells is associated with CD38-driven mitochondr- ial transfer.15 It is worth noting that this process seems to affect malignant cells preferentially and is not frequently observed in their normal counterparts. Therefore, a potential therapeutic window might be available through blockade of mitochondrial transfer.
Fatty acid metabolism and bone marrow adipocytes in acute myeloid leukemia
Work from Dr. Tabe’s and Dr. Andreeff’s laboratories has revealed other metabolic changes in AML, particularly focused on the role of adipocytes and fatty acid metabo- lism. Fat cells are a predominant type of stromal cell in aged human bone marrow. BMSC can promote AML survival
haematologica | 2019; 104(10)
1929