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The chemokine CXCL12 (also known as stromal cell derived factor [SDF-1]) 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 chemo-attractant 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.(7)

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 β-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 number of osteoclast precursors attracted into the bone in areas of myeloma plasma cell foci, thus mimicking the physiological process for recruiting osteoclast precursors.(9) They also suggested that CXCL12 could, in addition, enhance the pro-resorptive effects of the pro-resorptive cytokine RANKL.

Expression of CXCR4 and its ligand CXCL12 are likely to have varied and complex effects on tumor aggressiveness, ability to metastasize to bone, and impact on bone resorption when established in the bone environment. In the study of Diamond et al., RPMI-6228 cells were directly injected into the tibia and were predominantly restricted to this site for the duration of the study; thus, the role of CXCR4 signaling in either the initial mobilization or bone marrow targeting of myeloma cells to bone was not assessed. However, CXCR4 expression was consistently expressed (100%) in pleural effusion and peripheral blood of malignant plasma cells of patients. However, only 70% of patients had positive CXCR4 expression in bone marrow plasma cells, and these migratory multiple myeloma plasma cells had full functional ability to migrate in response to CXCL12.(10) This has been confirmed in a number of myeloma cell lines that showed a chemotactic response to CXCL12.(11) Thus, it is likely that stromal cell expression of CXCL12 plays a significant role in the progressive colonization of the skeleton during multiple myeloma progression.

Overexpression of CXC12 could have a number of different effects depending on context. Myeloma plasma cell overexpression of CXC12 would have the effect of abrogating CXC12 concentration gradients, thus reducing directed cell migration. Chemokines such as CXC12 exert their attractive effect by the establishment of a concentration gradient through which the target cell can migrate. Reduced expression of CXC12 by a cell population would be expected to enhance migratory responses. Clearly, high expression of CXCL12 by cells in a tumor is likely to cause either retention of these tumor cells in the primary site or to limit targeting to a secondary host site if high levels of CXCL12 are present in the circulation. Conversely, loss of CXCL12 expression is likely to increase sensitivity to CXCL12 expressed by host cells and thus to enhance intravasation and tissue targeting to host organs, such as bone, which present the tumor cell with a CXCL12 concentration gradient. Interestingly, the metastatic potential of breast cancer cells has found to be associated with the continuing expression of CXCR4 and the loss of expression (through epigenetic programming) of CXCL12.(12) Re-expression of CXCL12 induced increased proliferation and retention of tumor cells in the mammary fat pad, but markedly reduced the number of metastatic foci.(12) Thus, the source and levels of CXC12 in the local tissue milieu are critical determinants of whether cells are confined to the primary location or are mobilized into the vascular circulation. Once in the circulation it is likely that extravasation can be enhanced by expression of CXCL12 in target tissues, as is particularly relevant for bone.

In the study of Diamond et al., increased expression of CXCL12 was not found to alter the proliferation rates of RPMI-8226 cells in vitro or in vivo, and blocking of CXCL12 with a specific inhibitor did not decrease myeloma tumor burden. 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.(14) Similarly, breast cancer growth can be limited in bone by inhibiting bone resorption(15) or enhanced by increasing bone resorption in host tissues.(16) The lack of proliferative response to changes in levels of bone resorption in the study of Diamond et al.(8) may reflect the relative growth independence of the RPMI-8226 cell line as reflected in its ability to grow freely in in vitro culture systems. Induction of increased bone resorption through CXCL12 actions on osteoclast precursors could provide growth factors for the survival and proliferation of multiple myeloma plasma cells in the bone environment with secretion of factors such as IL-6 by osteoclasts(17) or by osteoclast-mediated release of growth factors such as IGF-1 from bone matrix, which has been shown to have strong effects on multiple myeloma plasma cell proliferation and survival.(18,19)

Consequently, study of the CXCL12/CXCR4 axis represents a fertile area of further study in gaining full understanding of the signaling pathways mediating the targeting of cancer and multiple myeloma to bone and in their impact on skeletal functions once established. As an indication that there is additional complexity in the role of CXCL12 signaling in osteoclast generation, it has been shown that selectively replacing the hematopoietic population with CXCR4-deficient cells results in increased (rather than decreased) osteoclast number and bone resorption.(20) There is the need for additional research that addresses the cell-specific roles of CXCL12 in osteoclast generation and in the tissue-specific targeting of multiple myeloma plasma cells and metastatic cancer cells.

REFERENCES

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