Mechanisms of Cancer Cell Metastasis to the Bone

A Multistep Process

Lalit R Patel; Daniel F Camacho; Yusuke Shiozawa; Kenneth J Pienta; Russell S Taichman

Disclosures

Future Oncol. 2011;7(11):1285-1297. 

In This Article

Types of Bone Metastatic Tumors

Leo Tolstoy began his 1873 work; 'Anna Karenina', with the line, "Happy families are all alike; every unhappy family is unhappy in its own way".[52] While the subject of Tolstoy's work is vastly different from that of this article, the underlying premise nevertheless applies. Normal bone marrow exists as a tissue with a defined architecture that is maintained by regulated turnover of its blood-forming and bone-forming compartments. By contrast, tumors developing from metastatic disseminations to the marrow exhibit a range of phenotypes with each type being driven by a unique set of mechanistic drivers.

A clear case for distinct phenotypes of bone metastatic lesions is presented by the existence of osteolytic (bone resorbing) and osteoblastic (bone forming) tumors. A third category of lesions is clinically evident in which a mixture of the two phenotypes is seen. The existence of mixed lesions suggests that the processes that regulate tumor-associated osteolysis and tumor-induced bone formation may occur together in bone metastasis and are not mutually exclusive activities. Furthermore, the relative activity of these two coexisting processes defines the global phenotype that a metastatic lesion ultimately adopts. Nevertheless, the mechanisms for driving tumor-associated osteolysis and tumor-induced bone formation are presented separately (Figure 5).

Figure 5.

A complex web of cancer–bone–T-cell interactions mediated by soluble factors, cell–cell interactions and downstream transcriptional networks that regulates osteolysis, osteoblastogenesis and the ultimate phenotype of bone metastatic lesions.
BMP: Bone morphogenetic protein; DTC: Disseminated tumor cell; LEF: Lymphoid enhancer binding; PKC: Protein kinase C; PTH: Parathyroid hormone; PTHrP: Parathyroid hormone-related peptide; SMAD: Mothers against decapentaplegic homolog; TCF: T-cell factor; Vit D: Vitamin D; WNT: Wingless-type MMTV integration site family.

Osteolytic metastases are a consequence of tumor-induced activation of bone-matrix resorption. Resorption of mineralized bone matrix is the natural function of osteoclasts, a multinucleated cell of hematopoietic origin residing in the bone. As reviewed by Roodman, tumor cell production of IL-1, IL-6, MIP1α or RANK ligand (RANKL) can activate osteoclastogenesis, a process involving the fusion of mononuclear macrophage-like osteoclast precursors into multinucleated cells.[6] These stimuli are transduced in osteoclast precursors by a combination of JUN kinase, NF-κB and calcineurin–NFAT pathways, which attenuate downstream transcriptional networks that regulate osteoclast maturation.[53] It has also been shown that IL-8 and CCL2 can induce precursors to undergo osteoclastogenesis through a RANKL-independent mechanism.[54]

In addition to stimulating the production of new osteoclasts, bone metastatic cancer cells co-opt cells of the bone marrow into activating bone resorption programs in existing osteoclasts. Specifically, the production of prostaglandins, parathyroid hormone, parathyroid hormone-related peptide, activated vitamin D, IL-6 and TNF by cancer cells may lead to tumor-induced increases in RANKL expression on osteoblasts and bone marrow stromal cells.[6] A less studied possibility involves the co-opting of T cells, which are ubiquitous in bone marrow but not present in immune-deficient animal models, to produce these osteoclast-activating secretions. In particular, tumor cell-derived IL-6, IL-1 and TGF-β can drive T-cell differentiation towards a Th17 secretory helper-cell phenotype capable of inducing osteoblastic RANKL and osteoclast activation through IL-17 production.[55] T cells may also be under-appreciated direct inducers of metastasis. Specifically, it was recently demonstrated that RANKL–RANK interaction between helper T cells and breast cancer cells promotes invasion, dissemination and metastasis formation from orthotopic syngeneic mouse mammary tumor virus–Erbb2 tumors in immunocompetent mice.[56] Recent work on Notch–Jagged interactions in the bone marrow suggests direct activation of osteolysis by cancer cells through this unique interaction.[31]

As reviewed by Logothetis and Lin, osteoblastic metastases are prevalent in advanced prostate cancer patients and induced by cancer cell interactions with osteoblasts and their progenitors by production of TGF-β, bone morphogenetic protein, IGF, FGF and WNTs.[57] Osteoblasts respond to morphogenetic factors by activating SMAD signaling, growth factors by MAPK and PKC signaling; and to WNT by acting β-catenin-regulated pathways. These pathways converge on and interact with the RUNX2 transcriptional network, which drives osteoblastic differentiation and proliferation. Cancer-induced WNT signaling in osteoblasts may also be mediated by lymphoid enhancer binding/T-cell factor transcriptional networks downstream of β-catenin dimerization with lymphoid enhancer binding/T-cell factor.[58,59] Prostate cancer cells also demonstrate osteomimicry by responding to growth factor stimulation via activation of CbfA, MSX and other osteoblastic transcription factors.[60] This would suggest that bone-forming tumors may also occur through differentiation of the cancer cells towards an osteoblastic bone-forming phenotype, which is a phenomenon that has been observed in the bone metastatic prostate cancer cell-line, C4-2b.[61]

A minimally studied category of cancer and bone interactions likely to contribute to metastatic tumor phenotype are those driven by steroid hormones. Given the predilection of prostate and breast cancers – both steroid-sensitive diseases – to form bone metastasis, there may be great value in understanding the extent to which mesenchymal and hematopoietic lineages of the bone marrow participate in metabolic interconversion and de novo synthesis of steroid hormones. In addition, it has been shown that hormone-sensitive prostate cancer cells can respond to steroid deprivation by activating de novo synthesis,[62] which implies that bone cells interacting with metastatic cancer may be stimulated by steroids produced locally by tumor cells. Research targeting the steroid-driven responses of blood-forming and bone-forming cells in the marrow may accordingly represent a largely unexplored area of high-value investigation.

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