Thalidomide treatment down-regulates SDF-1α and CXCR4 expression in multiple myeloma patients

Oliveira, Adriana Morgan; Maria, Durvanei Augusto; Metzger, Martin; Linardi, Camila C.G.; Giorgi, Ricardo Rodrigues; Moura, Fernanda Messeder; Martínez, Gracia; Bydlowski, Sérgio Paulo; Novak, Estela Maria

doi:10.1016/j.leukres.2008.09.018

Cited by 35 publications

(26 citation statements)

References 12 publications

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“…This cell line has been reported to express CXCR4 and respond with activation of downstream signaling. (13) However, in this cell line, CXCL12 expression did not seem to be associated with increased tumor burden either by direct proliferative action or by indirect stimulation mediated by increased osteoclast activity. This was a little surprising given the dependence of multiple myeloma establishment on bone resorption in some multiple myeloma models using implanted human bone as a host tissue in SCID mice for multiple myeloma plasma cells.…”

mentioning

confidence: 57%

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

Ooi

Dunstan

2009

Journal of Bone and Mineral Research

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The chemokine CXCL12 (also known as stromal cell derived factor ) and its receptor CXCR4 are strong candidates for regulating the mobilization and intravasation of primary cancer cells and their extravasation and formation of metastases in bone. CXCL12 has been reported to have chemo-attractive effects on both solid tumor-derived cancer cells (1) and multiple myeloma cells. (2,3) CXCL12 is produced in bone by bone marrow stromal cells, where it has a physiological role in establishing normal hematopoietic bone marrow colonization during development.(4) CXCL12 is a powerful chemoattractant for lymphocytes and monocytes. As such, CXCL12 can have the dual roles of attracting and retaining cells of these lineages in the bone environment.CXCL12 has also been implicated as a regulator of bone resorption through control of the migration of osteoclast precursors to resorption sites (5) and their maintenance within the bone environment.(6) CXCR4 is highly expressed in pre-osteoclasts and its expression decreases during the transition to mature osteoclasts.(7) CXCL12 has a role in attracting osteoclast precursors to areas of bone resorption through activation of the Akt signaling pathway (8) and may stimulate local proliferation and fusion of osteoclast precursors.(5) However, once osteoclast precursors are located in bone, RANKL seems to initiate all aspects of the resorption process (osteoclast differentiation, TRACP activity, cathepsin K activity, bone pit formation), and these effects seem independent of CXCL12. Multiple myeloma plasma cells and solid cancer cells, when metastasized to bone, are able to hijack the normal regulatory pathways to support their own growth. Extensive osteoclastic bone resorption, with the resultant bone destruction and associated morbidity, is characteristic of multiple myeloma. The paper of Diamond et al., (8) published in the Journal of Bone and Mineral Research this month, provides convincing evidence that, in multiple myeloma, plasma cell-expressed CXC12 plays a role in inducing the enhanced bone resorption characteristic of this disease.Diamond et al. (8) evaluated the effects of CXCL12 overexpression by the multiple myeloma cell line, RPMI-8226, in a murine intratibial model of multiple myeloma. They showed that increased expression of CXCL12 is associated with increased osteoclast numbers and bone loss. Conversely, dosing the mice with an inhibitor of CXCL12/ CXCR4 signaling (T140) can inhibit the increased bone resorption and the bone loss induced by the parental RPMI-8226 cells. To support the more general relevance of these observations to human multiple myeloma, the authors showed high CXCL12 expression in a primary cell isolate of CD138 + plasma cells from a multiple myeloma patient and found that CXCL12 blood levels correlated with levels of the bone resorption marker b-crosslaps in a group of normal, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma patients. The authors suggested that CXCL12 could be increasing bone resorption by increasing the ...

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confidence: 57%

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

Ooi

Dunstan

2009

Journal of Bone and Mineral Research

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“…IL6, which promotes growth of myeloma cells and counteracts apoptotic signals by regulating BCL2 family [49], was enhanced by BMP treatment in our conditions. It is known that resistance to apoptosis, common in myeloma cells, depends on activated intracellular pathways in the particular circumstances and constitutive expression of molecules acting at cellcycle checkpoints [6][7][8][9]23]. Relatively high basal apoptotic rate and the slow division of myeloma cells in culture may explain why BMPs exhibited the protective role on myeloma cell lines only in conditions of bortezomib-or TRAIL-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple antiapoptotic signaling mechanisms contribute to the accumulation of myeloma cells within the BM and account for their resistance to chemotherapy [4][5][6]. The most important molecules expressed by myeloma cells which promote their survival and proliferation are anti-apoptotic members of the BCL2 family and a number of growth factors, adhesion molecules and cytokines, especially IL6 [6][7][8][9]. Several cytokines have also been reported to inhibit myeloma cell growth in different culture conditions, including bone morphogenetic proteins (BMPs) [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…Despite BMP proapoptotic action on several myeloma cell lines and primary myeloma cells in vitro [12][13][14], other studies on different types of malignancies showed their tumor-promoting effects in vitro and in vivo [15][16][17][18][19][20]. Importantly, in vitro effects of BMPs need to be further investigated on human MM samples because primary myeloma cells in culture conditions are removed from the interactions with other cells within BM microenvironment which may regulate their response [7][8][9]. In addition, primary myeloma cells have poor survival and growth in culture [21], so the in vitro observations may not reveal the true biological role of BMPs in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Bone morphogenetic proteins and receptors are over-expressed in bone-marrow cells of multiple myeloma patients and support myeloma cells by inducing ID genes

et al. 2010

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“…Treatment of myeloma cell lines with thymoquinone (the major active component of the medicinal herb Nigella sativa Linn) results in decreased CXCR4 expression, possibly by inhibiting CXCL12 [29]. This is further supported by studies that demonstrate that the CXCR4 inhibitor AMD3100 disrupts the interaction between the myeloma cells and the bone marrow, enhancing their chemosensitivity [30] Finally, thalidomide therapy has been shown to decrease CXCR4 expression by myeloma cells in patients undergoing treatment, compared to their original diagnostic specimen [31]. The role that these new emerging markers will play in the clinical lab is uncertain and will require additional study.…”

Section: Emerging Markers-cues From Preclinical Modelsmentioning

confidence: 95%

Utility of Flow Cytometry to Classify Abnormal Plasma Cell Populations in Marrow Samples Collected from Patients with Putative Plasma Cell Neoplasms

Singh¹,

Yohe²,

Baughn³

et al. 2012

OJBD

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Plasma cell neoplasms comprise a spectrum of diseases that include monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Flow cytometric immunophenotyping has become an invaluable tool as an ancillary and diagnostic test for hematologic malignancies and is being used with increasing frequency in the diagnosis and monitoring of plasma cell neoplasms. As multiparameter flow cytometry has evolved, faster fluidics and detection systems facilitate the screening of a large number of events and the detection of multiple antigens simultaneously. This review addresses the approaches used to evaluate clonal plasma cell neoplasms and describes different surface and cytoplasmic markers and techniques that are important for the study of these diseases.

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Thalidomide treatment down-regulates SDF-1α and CXCR4 expression in multiple myeloma patients

Cited by 35 publications

References 12 publications

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

Bone morphogenetic proteins and receptors are over-expressed in bone-marrow cells of multiple myeloma patients and support myeloma cells by inducing ID genes

Utility of Flow Cytometry to Classify Abnormal Plasma Cell Populations in Marrow Samples Collected from Patients with Putative Plasma Cell Neoplasms

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