Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.

/pdf/ccl2-induced-chemokine-cascade-promotes-breast-cancer-4dv8rj7ut2.pdf

CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.

Until recently, inflammatory chemokines were viewed mainly as indispensable “gate keepers” of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.

https://downloads.hindawi.com/journals/mi/2014/292376.pdf

The inflammatory chemokine CCL5 and cancer progression.

It is clear from large clinical studies that selected chemokine receptors are often up-regulated in a large number of common human cancers, including those of the breast, lung, prostate, colon, and melanoma. Chemokine receptors and their corresponding chemokine ligands have been demonstrated to play a number of nonredundant roles in cancer metastasis to vital organs as well as regional lymph nodes, the most frequent site of cancer metastasis. Chemokine receptors may potentially facilitate tumor dissemination at several key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, angiogenesis, proliferation, and protection from the host response via activation of key survival pathways such as phosphatidylinositol-3 kinase and Akt. It is interesting that many of these roles are reminiscent of their functions in leukocyte and stem cell trafficking. Lastly, we discuss therapeutic applications for chemokine receptor antagonists in cancer therapy.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.1105633

Chemokines, chemokine receptors, and cancer metastasis

Multiple myeloma (MM) is a neoplasm of post-germinal center, terminally differentiated B cells. It is characterized by a multifocal proliferation of clonal, long-lived plasma cells within the bone marrow (BM) and associated skeletal destruction, serum monoclonal gammopathy, immune suppression, and end-organ sequelae. MM is preceded by an age-progressive premalignant condition termed monoclonal gammopathy of undetermined significance. Unlike the genomes of most hematological malignancies, and similar to those of solid-tissue neoplasms, MM genomes are typified by numerous structural and numerical chromosomal aberrations as well as mutations in a number of oncogenes and tumor-suppressor genes, some of which have been linked to disease pathogenesis and clinical behavior. Recent studies have also defined the importance of interactions between the MM cells and their BM microenvironment, dysregulation in signaling pathways and in a specialized subpopulation of cells within the tumor (termed myeloma cancer stem cells) for tumor cell growth and survival, and the development of resistance to therapy.

Pathogenesis of Myeloma

https://www.exphem.org/article/S0301-472X(04)00433-3/pdf

MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells

The present invention relates to piperazine derivatives of formulae Ia, Ib, Ic and Id, where Rla, Rlb, R2, R3, R4, R5, R6, R9, R10 and Y are as defined herein, and their use to treat multiple myeloma.

Chemokine inhibiting piperazine derivatives and their use to treat multiple myeloma

L'invention porte sur des derives de la piperazine de formules Ia, Ib, Ic et Id, dans lesquelles Rla, Rlb, R2, R3, R4, R5, R6, R9, R10 et Y sont definis dans la description et sur leur utilisation pour traiter les myelomes multiple.

Richard Horuk

Papers

MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells

Chemokine inhibiting piperazine derivatives and their use to treat multiple myeloma

Derives de la piperazine inhibiteurs de la chemokine et leur utilisation pour traiter les myelomes multiples