Retinoic acid, CYP26, and drug resistance in the stem cell niche

• Published in: Experimental hematology Vol. 54; pp. 17 - 25
• Main Authors: Alonso, Salvador, Jones, Richard J., Ghiaur, Gabriel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2017
• Subjects: Antineoplastic Agents - therapeutic use; beta Catenin - genetics; beta Catenin - metabolism; Cytochrome P450 Family 26 - genetics; Cytochrome P450 Family 26 - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - genetics; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - pathology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasm, Residual; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction; Stem Cell Niche - drug effects; Stem Cell Niche - genetics; Tretinoin - metabolism; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics
• ISSN: 0301-472X; 1873-2399; 1873-2399
• DOI: 10.1016/j.exphem.2017.07.004

•The bone marrow microenvironment metabolizes retinoids via CYP26 and creates low-retinoid niches.•Normal hematopoietic stem cells (HSCs) are protected in these low-retinoid BM niches.•Malignant HSCs hijack these niches and evade chemotherapy.•Malignant clones reinforce these niches via increased expression of CYP26.•Similar mechanisms protect solid tumor cells metastatic to the bone. The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.