**6. Cancer stem cell phenotype and tumor microenvironment**

Recent knowledge supports the hypothesis that altered BM microenvironments participate in both mechanisms leading to tumor progression; induction of stem cell features and stimulation of angiogenesis. Cancer stem cell phenotypes may be a plastic state induced in cancer cells depending upon microenvironmental signals, such as hypoxia. Hypoxia has a great impact on the production of angiogenic factors but it is also a crucial regulator of the stem cell phenotype. Several reports have shown that hypoxia and HIFs are involved in maintaining a stem-like state in normal tissues [138]. One example can represent hematopoietic stem cells that reside in regions regulated by oxygen tension. It is hypothesized that undifferentiated phenotypes of these cells relies on HIF activity in hypoxic areas. Hypoxic areas in tumors might be an analog to stem cell niches in normal tissues. Furthermore, Yoshida *et al.* (2009) have shown that hypoxic conditions significantly improve generation of iPSC [139]. Growing knowledge of cancer stem cell biology suggests that hypoxia may act as a critical regulator of the cancer stem cell phenotype.

Series of experiments have demonstrated that hypoxia is responsible for altering the cellular phenotype by causing an increase in proliferation, self-renewal and upregulation of stem cell genes in both CSC and non-CSC. Several groups have shown that hypoxia can regulate histone methylation and thus alter the epigenetic status of cancer cells [140-142]. Tumor hypoxia also correlates with poor outcome of patients. HIFs were shown to induce the embryonal stem celllike transcriptional program, including *OCT4, NANOG, SOX2, KLF4, MYC*, and micro‐ RNA-302 in cancer cell lines of prostate, brain, kidney, cervix, lung, colon, liver and breast tumors [143]. Hypoxic microenvironment potentiates biological effect of Notch signaling in adenocarcinoma of the lung or alters gene expression of neuroblastoma cells to induce more immature phenotype [144, 145]. CD133, a cancer stem cell marker, has been reported by several groups to be upregulated under hypoxic conditions [146, 147]. McCord et al. [2009] showed that hypoxia not only increased the sub-population of glioblastoma cells positive for CD133, but also enhanced expression of other stem cell markers, such as SOX2, OCT4 and nestin [148]. Low oxygen levels induced also HIF-2α expression that can increase the expression of stem cell-associated genes and confer tumorigenic potential to non-CSC [140].

**Acknowledgements**

**Author details**

Hana Šváchová1

thank Andrea Knight for proof reading the manuscript.

, Sabina Sevcikova1

\*Address all correspondence to: roman.hajek@fno.cz

saryk University, Czech Republic

2005 Oct;80(10):1371-82.

vest. 1977 Oct;60(4):846-54.

Cancer Res. 1968 Nov;28(11):2187-96.

public,, Czech Republic

**References**

This work was supported by grants from The Ministry of Education, Youth and Sports: MSM0021622434 and Czech Science Foundation GAP304/10/1395. The authors would like to

Heterogeneity and Plasticity of Multiple Myeloma

http://dx.doi.org/10.5772/55365

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and Roman Hájek1,2

1 Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Ma‐

2 Faculty of Medicine, University of Ostrava and University Hospital of Ostrava, Czech Re‐

[1] Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc.

[2] Richardson P, Anderson K. Thalidomide and dexamethasone: a new standard of care

[3] Hamburger A, Salmon SE. Primary bioassay of human myeloma stem cells. J Clin In‐

[4] Bergsagel DE, Valeriote FA. Growth characteristics of a mouse plasma cell tumor.

[5] Park CH, Bergsagel DE, McCulloch EA. Mouse myeloma tumor stem cells: a primary

[6] Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, et al. Characteri‐ zation of clonogenic multiple myeloma cells. Blood. 2004 Mar;103(6):2332-6.

[7] Yaccoby S, Epstein J. The proliferative potential of myeloma plasma cells manifest in

[8] Pfeifer S, Perez-Andres M, Ludwig H, Sahota SS, Zojer N. Evaluating the clonal hier‐ archy in light-chain multiple myeloma: implications against the myeloma stem cell

cell culture assay. J Natl Cancer Inst. 1971 Feb;46(2):411-22.

the SCID-hu host. Blood. 1999 Nov;94(10):3576-82.

hypothesis. Leukemia. 2011 Jul;25(7):1213-6.

for initial therapy in multiple myeloma. J Clin Oncol. 2006 Jan;24(3):334-6.

The BM microenvironment of MM is also hypoxic, and myeloma PCs are long term exposed to low oxygen levels. Tumor adaptation to hypoxia is mediated by the production of HIF-1 [149]. Both HIF-1α and HIF-2α have been reported to be activated in MM patients resulting in stimulation of angiogenesis [150]. Although a role of BM microenvironment is generally recognized as a crucial factor affecting myeloma development and support progression, it is surprising that an importance of hypoxic microenvironment for modulation of plasma cell phenotype have never been studied in MM.
