SDF-1 Inhibition Targets the Bone Marrow Niche for Cancer Therapy

Roccaro, Aldo M.; Sacco, Antonio; Purschke, Werner G.; Moschetta, Michele; Maasch, Christian; Zboralski, Dirk; Zöllner, Stefan; Vonhoff, Stefan; Mishima, Yuji; Maiso, Patricia; Reagan, Michaela R.; Lonardi, Silvia; Ungari, Marco; Facchetti, Fabio; Eulberg, Dirk; Kruschinski, Anna; Vater, Axel; Rossi, Giuseppe; Klussmann, Sven; Ghobrial, Irène M.

doi:10.1016/j.celrep.2014.08.042

Cited by 119 publications

(121 citation statements)

References 42 publications

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“…Importantly, blockade of the CXCL12/CXCR4 pathway in murine MM models results in decreased MMC homing and growth, thus halting disease progression. 129 …”

Section: Soluble Factorsmentioning

confidence: 99%

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Pathogenesis beyond the cancer clone(s) in multiple myeloma

Bianchi

Munshi

2015

Blood

242

224

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Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. (Blood. 2015;125(20):3049-3058) Characteristics of the myeloma cancer clone Ontogenesis of myelomaMultiple myeloma (MM) represents the far end of the spectrum of B cell-derived neoplasms. It is the neoplastic counterpart of terminally differentiated, immunoglobulin-producing, long-lived plasma cells (PCs). Long-lived PCs are a subset of PCs characterized by long-term (months to years) survival within the bone marrow (BM) and thought to be key for immunologic memory.1,2 Based on the sequencing of the immunoglobulin heavy chain (IgH) variable region of MM cells (MMCs), the first oncogenic events in MM appear to occur in the germinal center, likely during the processes of isotype class switching and somatic hypermutation, which are, by nature, mutation prone. 3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC (Figure 1). 4 There is ongoing debate regarding the identity of the MM stem cells. Different groups have shown that both CD138 1 and CD192 cells are capable of tumorigenesis in mouse models.However, CD138 1 tends to lose self-renewing potential after a few cycles of serial transplantation, whereas the putative B-cell stem clone was never proved to be clonally related to its putative CD138 1 progeny.Overall, modification in the cytokine composition of the media used to maintain CD138 1 ex vivo successfully overcame the first issue, suggesting that the MM stem cell may be CD1381 . 5Ev...

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“…Importantly, blockade of the CXCL12/CXCR4 pathway in murine MM models results in decreased MMC homing and growth, thus halting disease progression. 129 …”

Section: Soluble Factorsmentioning

confidence: 99%

“…128,129 Signaling through CXCL12-CXCR4 results in modest direct effect on MM proliferation and resistance to dexamethasone. However, CXCL12 induces IL-6 and VEGF secretion by BMSCs, thus indirectly promoting MMC proliferation, antiapoptosis, neoangiogenesis, and resistance to therapy.…”

Section: Soluble Factorsmentioning

confidence: 99%

Pathogenesis beyond the cancer clone(s) in multiple myeloma

Bianchi

Munshi

2015

Blood

242

224

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“…With this technique, it is possible to visualize cancer cells that home to the BM and establish contact with osteoblasts or the vasculature (1,2,10,(14)(15)(16). However, this technique is invasive and has limitations: (i) it is not quantitative; (ii) it cannot be used to analyze for screening studies such as drug screens or functional genomic studies such as shRNA or CRISPR screens; and (iii) it does not allow the use of primary cancer cells, as it requires a large number of tumor cells to be injected i.v.…”

Section: Introductionmentioning

confidence: 99%

“…MM represents a good model to examine homing to the BM as it presents with multiple lesions in the BM by the time patients present with their disease (1,2). The interaction between tumor cells and the surrounding BM microenvironment is essential for MM cell proliferation and dissemination, leading to disease progression and chemoresistance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). For instance, the neutralization of CXCL12 within the BM niche reduces MM cell dissemination within the BM, leading to inhibition of MM disease progression (13).…”

Section: Introductionmentioning

confidence: 99%

Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model

Sacco

Roccaro

et al. 2016

Cancer Research

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Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. Cancer Res; 76(2); 463-71. Ó2016 AACR.

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“…91,92 Inhibition of CXCL12 using NOX-A12 (olaptesed pegol), a high-affinity anti-SDF-1a pegylated mirror-image L-oligonucleotide, triggers MM cytotoxicity in preclinical studies. 93 In a phase 2a trial in RRMM, combination NOX-A12/bortezomib/dexamethasone achieved a PFS of 6.5 months and a 73% ORR, even in high-risk and/or bortezomib-refractory patients. 94 The regimen was well tolerated, and this combination is now entering phase 3 trials.…”

Section: Cxcl12/cxcr4 Axis Inhibitorsmentioning

confidence: 99%