Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

Figures & data

Table I. Marrow niche characteristics of normal and cancer stem cells.

	Endosteal/osteoblastic niche	Vascular/endothelial niche	References
Location in marrow	10 μm layer next to bone surfaces	Hematopoietic tissue	Lord (1990), Kiel et al. (2005)
Normal and cancer stem cell replication	Mainly self-renewal of stem cells	Mainly asymmetric division (produce differentiated progeny)	Arai and Suda (2007), Eliasson and Jönsson (2010)
Normal stem cell activity	Quiescent	Rapid blood cell expansion	Moore and Lemischka (2006), Nagasawa (2006)
Cancer stem cell activity	Quiescent	Rapid primary/metastatic tumour spread	Sipkins et al. (2005), Ishikawa et al. (2007), Medinger and Mross (2010)
O2 pressure (% atmospheric)	0.1–1%	∼7%	Parmar et al. (2007), Harrison (2002)
O2 enhancement ratio (OER, low-LET)	1.1–1.4	2.5	Thoday and Read (1949), Richardson (2008)

Figure 1. Schematic diagrams (not to scale) depict trabecular marrow cavities that in reality are usually interconnecting. Sub-figure (A) names the anatomical parts of a marrow cavity and shows the partitioned hematopoietic targets for leukemia, consisting of the endosteum and central hematopoietic marrow and (B) shows the partitioned peripheral marrow targets for bone cancer consisting of quiescent surface peripheral marrow (QSPM) and forming surface peripheral marrow (FSPM): the latter target could include the bone remodelling compartment (BRC).

Table II. Characteristics of different types of leukaemia, namely their relative incidence levels of spontaneous occurrence at different stages of human development and the stem or progenitor cells from which the leukaemic types originate (Ries et al. 2007). Note that the Philadelphia chromosome is not only found in children with ALL but also found in adults with ALL, and occasionally those with AML (Jamieson et al. 2004)^a.

	Acute myeloid leukaemia (AML)	Chronic myeloid leukaemia (CML)	Acute lymphocytic leukaemia (ALL)	Chronic lymphocytic leukaemia (CLL)
Spontaneous incidence	Most common acute leukaemia in adults	Occurs in middle aged and elderly adults	Majority of childhood leukaemia	Rare under 45 years of age
Hematopoietic stem cell (HSC) and its leukaemic progenitors.	HSC, myeloid progenitors^a	HSC, granulocyte-macrophage progenitors. Usually Philadelphia chromosome translocation present^a	HSC, lymphoid progenitors. Majority are of B cell lineage^a	HSC, lymphoid progenitors. Great majority are of B cell lineage

Table III. Comparison of the percentage incidence rates for spontaneous and radiation-induced leukaemia (assuming 0% radiation-induced CLL). The spontaneous incidence rates are those of England and Wales from NRPB (2003)^a as given in their Table 1.1. The low-LET incidence rates are those of the UK population, also from NRPB (2003)^a as evaluated in their Table 4.3 based on the BEIR V (1990) risk model. The high-LET incidence rates are those of Danish Thorotrast patients (Visfeldt and Andersson 1995)^b.

	AML	CML	ALL	CLL
Spontaneous^a	27%	9%	9%	55%
Low-LET radiation^a	53%	22%	25%	0%
Thorotrast (high-LET)^b	80%	15%	5%	0%

AML, Acute myeloid leukaemia; CML, Chronic myeloid leukaemia; ALL, Acute lymphocytic leukaemia; CLL, Chronic lymphocytic leukaemia.

Table IV. Characteristics of different types of spontaneous and radiation-induced bone tumours (Ewing's sarcoma is not associated with radiation^a) including their relative incidence levels of spontaneous occurrence at different stages of human development, the stem or progenitor cells from which the bone tumour types originate and their location in the skeleton (Gurney et al. 1999).

	Osteosarcoma	Chondrosarcoma	Fibrosarcoma	Ewing's sarcoma^a
Spontaneous childhood incidence	Most common	Rare	Almost unknown	2^nd most common
Spontaneous aged adult incidence	2^nd most common	Most common	Rare	Rare
Mesenchymal stem cell (MSC) and its progenitors.	MSC, osteoblastic progenitors	MSC, cartilage progenitors	MSC, stromal progenitors	MSC neural crest origin
Usual skeletal location	Metaphysis of long bones	Pelvis, leg bone and arm bone.	Metaphysis or diaphysis of long bones	Extremities and central axis
Usual bone type	Intramedullary and periosteal (Rare: intracortical)	Intramedullary	Intramedullary and periosteal	Intramedullary and periosteal

Table V. Comparison of the percentage bone tumour incidence rates that occur spontaneously or are radiation-induced, including malignant fibrous histiocytoma (MFH). Other types of spontaneous malignant bone tumours than are named here make up 14% of tumour types examined in ‘all population’ but only 3% of those aged 0–20 y (Unni 1996)^a. The Paget's disease study was by Schajowicz et al. (1983)^b, the radium values were reported by Gössner (1999)^c, the external irradiation of adults was based on the combined studies of Huvos (1991) and Unni (1996)^d. Tucker et al. (1987)^e assessed the bone cancers developed after the radiotherapy treatment of childhood cancer.

	Osteosarcoma	Chondrosarcoma	Fibrosarcoma/MFH	Ewing's sarcoma	Number of individuals
Spontaneous, all population^a	41%	25%	8%	12%,	5,676
Spontaneous, 0–20 years old^a	61%	4%	4%	28%	–
Paget's disease, adults^b	63%	8%	27%	0%	62
^224Ra, ^226–228Ra, mainly adults^c	59%	7%	30%	0%	92
External radiation, mainly adults^d	63%	4%	33%	0%	246
External radiation of children^e	69%	17%	5%	5%	64

Lord BI. 1990. The architecture of bone marrow cell populations. The International Journal of Cell Cloning 8:317–331.

 PubMedGoogle Scholar

Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–1121.

 PubMed Web of Science ®Google Scholar

Arai F, Suda T. 2007. Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Annals of the New York Academy of Sciences 1106:41–53.

 PubMed Web of Science ®Google Scholar

Eliasson P, Jönsson J-I. 2010. The hematopoietic stem cell niche: Low in oxygen but a nice place to be. Journal of Cell Physiology 222:17–22.

 PubMed Web of Science ®Google Scholar

Moore KA, Lemischka IR. 2006. Stem cells and their niches. Science 311:1880–1885.

 PubMed Web of Science ®Google Scholar

Nagasawa T. 2006. Microenvironmental niches in the bone marrow required for B-cell development. Nature Reviews Immunology 6:107–116.

 PubMed Web of Science ®Google Scholar

Sipkins DA, Wei X, Wu JW, Runnels JM, Côté D, Means TK, Luster AD, Scadden DT, Lin CP. 2005. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435:969–973.

 PubMed Web of Science ®Google Scholar

Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD. 2007. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nature Biotechnology 25:1315–1321.

 PubMed Web of Science ®Google Scholar

Medinger M, Mross K. 2010. Clinical trials with anti-angiogenic agents in hematological malignancies. Journal of Angiogenesis Research. 2:10 (doi:10.1186/2040-2384-2-10).

 PubMedGoogle Scholar

Parmar K, Mauch P, Vergilio JA, Sackstein R, Brown JD. 2007. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proceedings of the National Academy of Sciences of the USA 104:5431–5436.

 PubMed Web of Science ®Google Scholar

Harrison JS. 2002. Oxygen saturation in the bone marrow of healthy volunteers. Blood 99:394.

 PubMed Web of Science ®Google Scholar

Thoday JM, Read J. 1949. Effect of oxygen on the frequency of chromosomal aberrantions produced by X-rays. Nature 160:608–609.

 Google Scholar

Richardson RB. 2008. Age-dependent radiation effects to normal and diseased coronary arteries – part 3: Oxygen effect and its implications on high- and low-LET dose. International Journal of Radiation Biology 84:858–865.

 PubMed Web of Science ®Google Scholar

Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Horner MJ, Howlader N, Eisner MP, Reichman M, Edwards BK. 2007. SEER Cancer Statistics Review, 1975–2004. Bethesda, MD: National Cancer Institute; Accessed 10 October 2007 from the website: http://seer.cancer.gov/csr/1975_2004/

 Google Scholar

Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. 2004. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. The New England Journal of Medicine 351:657–667.

 PubMed Web of Science ®Google Scholar

Visfeldt J, Andersson M. 1995. Pathoanatomical aspects of malignant haematological disorders among Danish patients exposed to thorium dioxide. Acta Pathologica, Microbiologica et Immunologica Scandinavica 103:29–36.

 PubMed Web of Science ®Google Scholar

Gurney JG, Swensen AR, Bulterys M. 1999. Malignant bone tumours. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995In: Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, editors. NIH Pub. No. 99–4649. Bethesda, MD: National Cancer Institute; pp 17–34.

 Google Scholar

Unni KK. 1996. Dahlin's bone tumours. General aspects and data on 11,087 cases. 5th ed. Philadelphia, New York: Lippincott-Raven;

 Google Scholar

Schajowicz F, Santini Araujo E, Berenstein M. 1983. Sarcoma complicating Paget's disease of bone. A clinicopathological study of 62 cases. Journal of Bone and Joint Surgery – British Volume 65:299–307.

 PubMedGoogle Scholar

Gössner W. 1999. Pathology of radium-induced bone tumors: New aspects of histopathology and histogenesis. Radiation Research 152(Suppl.):12–15.

 Google Scholar

Huvos AG. 1991. Bone tumors: Diagnosis, treatment and prognosis. Philadelphia: WB Saunders Co;

 Google Scholar

Tucker MA, D'Angio GJ, Boice JD Jr, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W, Hoover RN, Fraumeni JF. 1987. Bone sarcomas linked to radiotherapy and chemotherapy in children. The New England Journal of Medicine 317:588–593.

 PubMed Web of Science ®Google Scholar