Associate editor: B. TeicherTargeting tumor–stromal interactions in bone metastasis
Introduction
Metastasis to the bone is one of the most common and devastating complications in patients with advanced cancers of the breast, prostate or lung. Also manifests in other cancers (thyroid, renal cell, colon, esophageal or rectum), bone metastasis is a pathological process notable for the ability of tumor cells to exploit endogenous stromal environments and coerce other host cell types into cooperation. Despite gross morphological differences between the bone and the soft tissues from which bone metastases originate, the underlying molecular interactions between disseminated tumor cells (DTCs) and bone tissues make bone a particularly attractive niche for the growth of metastatic lesions. Lending credence to this idea, many of the genes associated with breast cancer metastasis to bone are surface interaction proteins or secreted growth factors, demonstrating that mechanisms extrinsic to the tumor cells are paramount to metastatic progression (Kang et al., 2003). From instructing the pre-metastatic niche to establishing a vicious cycle of bone remodeling and tumor growth, tumor–stromal interactions are crucial to metastatic expansion in bone. Although this tumor–stromal relationship endows resistance to many conventional therapeutic approaches, exploiting the crosstalk between tumor cells and the bone stromal compartment may provide an effective mean to thwart cancer metastasis to bone.
Myriad evidence has emerged within the last decade which indicates the need to target early tumor–stromal interactions (pre-metastatic niche conditioning, seeding and dormancy) to best treat bone metastasis. Current treatments target overt, established metastases and the symptoms associated with increased bone remodeling (Roodman, 2004, Weilbaecher et al., 2011, Ell and Kang, 2012). Meanwhile, recent research implicates multiple novel therapeutic opportunities within the priming of the pre-metastatic niche, metastatic seeding, micrometastatic dormancy and immune surveillance (Sipkins et al., 2005, Catena et al., 2010) (Table 1). Knowledge regarding the later steps of metastasis, such as bone-remodeling and the establishment of an immune-suppressive environment, has also advanced in recent years and future treatments may strive to transform overt metastasis into a chronic, treatable condition. Furthermore, select patients are receptive to current immune-modulatory therapies, yet the factors that govern a positive response are unknown and require further research to elucidate.
Section snippets
Educating the bone: forming the pre-metastatic niche
The discovery that primary tumor cells are able to instruct the adaptation of foreign sites for future colonization represents a paradigmatic shift in cancer research. Rather than a stochastic process through which a certain proportion of CTCs is able to colonize sites of distant metastasis, the ability of the primary tumor to influence future routes of metastasis both supports Stephen Paget's well established seed and soil hypothesis (Paget, 1989), and presents new opportunities for
Metastatic seeding: survival in circulation, homing, and attaching to bone parenchyma
Metastatic cells are especially vulnerable during transit from the primary tumor to distant metastatic sites. Selective pressures placed on metastatic cells during seeding and extravasation result in an high attrition rate — only an estimated 0.2% of experimentally introduced circulating tumor cells (CTC) successfully accomplish distant colonization (Chambers et al., 2002). During the traverse from primary tumor to bone marrow, circulating tumor cells (CTCs) must both evade immune surveillance
Metastatic niches and metastatic dormancy
The existence of dormant cells in bone metastasis has been long hypothesized; however, research on the molecular regulation of metastatic dormancy only started to gain momentum in recent years (Aguirre-Ghiso, 2007). Existing knowledge regarding dormancy indicates that metastatic quiescence is largely dependent on the stromal environment and specifically on the niche where the DTCs reside. How stromal cells affect cell dormancy and the extent to which either the HSC niche or perivascular niche
The osteolytic/osteogenic axis in bone metastasis
The bone is best known for two of the most vital roles in normal physiology: structural support and hematopoiesis. The ability of bone metastases to subvert both processes is the primary cause of morbidity and mortality in cancer patients with bone metastasis. The bone is in a constant state of dynamic remodeling by a balance between osteolytic and osteogenic programs. Metastatic cancer cells often successfully exploit the normal bone homeostatic process and tip the equilibrium toward either
Current therapies targeting bone remodeling
Therapeutics targeting the bone resorptive cycles of myeloma and breast cancer are a palliative rather than a curative approach toward treatment of bone metastasis as these therapies slow osteoclast activity and thereby extend patient lifespan. Anti-resorptive therapies similarly extend time to relapse in bone when tested in patients with osteoblastic metastases, demonstrating that the cross-communication between osteoclasts and osteoblasts is important to progression of both subtypes of bone
Immune regulation and immune suppression
The immune system plays a critical role in each step of tumor progression — from the original transformation to macrometastatic progression, immune suppression and/or immune evasion is required for the survival and expansion of tumors. In a successful metastatic progression, the immune system is often reconfigured to become a malignant accomplice able to assist in multiple functions. Several programs, such as NK cell- or effector T cell-mediated lysis, are antagonistic to progression. However
Stromal-endowed therapeutic resistance
Bone stromal cells not only participate in the pathogenesis of bone lesions, but also make them refractory to traditional chemotherapies. Chemotherapy has no effect on dormant DTCs in the bone marrow (Braun et al., 2000), and many groundbreaking studies have attributed this phenomenon to various stromal cell programs mediating cancer cell survival. Acharyya et al. found that a chemoresistance cycle was instated when chemotherapy elicits TNFα secretion from the stroma — this then increases
Conclusions and future directions
The understanding of bone metastasis has progressed considerably in recent years, with particular emphasis on the contribution of the host to metastatic progression. Bone metastases often acquire a unique set of molecular traits which are able to temper the bone microenvironment to facilitate the growth of metastatic tumors in bone. These traits are only part of the pathogenesis of bone metastasis — contributions of associated stromal cells are active participants in every step of progression.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
We thank the members of our laboratories for helpful discussions and critical reading of the manuscript. We also apologize to the many investigators whose important studies could not be cited directly here owing to space limitations. Research in the authors' laboratory was supported by grants from the Brewster Foundation, the Champalimaud Foundation, Department of Defense, Komen for the Cure, and the National Institutes of Health to Y.K.
References (191)
Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: A vicious cycle between bone destruction and myeloma expansion
Blood
(2004)- et al.
A CXCL1 paracrine network links cancer chemoresistance and metastasis
Cell
(2012) - et al.
Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche
Cell
(2004) - et al.
Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway
Cancer Cell
(2004) - et al.
Osteoclast formation and bone resorption are inhibited by megakaryocytes
Bone
(2006) - et al.
Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease
Bone
(2003) - et al.
Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells
Blood
(2012) - et al.
Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts
J Urol
(1996) - et al.
CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy
Neoplasia
(2012) - et al.
Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation
Cell
(1997)
Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer
Blood
Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-l-leucine
Neoplasia
Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase
Neoplasia
Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose
J Biol Chem
Inhibition of spontaneous breast cancer metastasis by anti-Thomsen–Friedenreich antigen monoclonal antibody JAA-F11
Neoplasia
Reduced thoracic vertebrae metastases following post mastectomy parasternal irradiation
Int J Radiat Oncol Biol Phys
Systemic spread is an early step in breast cancer
Cancer Cell
Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen
Urology
Tumor cell dissemination: Emerging biological insights from animal models and cancer patients
Cancer Cell
A multigenic program mediating breast cancer metastasis to bone
Cancer Cell
PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: Evidence for cooperation between E-selectin ligands and alpha4 integrin
Blood
Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis
Cancer Cell
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation
Cell
Therapeutic targeting of a stem cell niche
Nat Biotechnol
Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling
J Cell Biol
Models, mechanisms and clinical evidence for cancer dormancy
Nat Rev Cancer
Runx2 association with progression of prostate cancer in patients: Mechanisms mediating bone osteolysis and osteoblastic metastatic lesions
Oncogene
Radiation treatment of prostate bone metastases and the biological considerations
Adv Exp Med Biol
Platelet and osteoclast beta3 integrins are critical for bone metastasis
Proc Natl Acad Sci U S A
Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression
Nat Med
Runx2 transcriptome of prostate cancer cells: Insights into invasiveness and bone metastasis
Mol Cancer
Hematogenous and lymphatic tumor cell dissemination may be detected in patients diagnosed with ductal carcinoma in situ of the breast
Breast Cancer Res Treat
Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells
Cancer Res
Definition of molecular determinants of prostate cancer cell bone extravasation
Cancer Res
Suppression of NK cell activity and of resistance to metastasis by stress: A role for adrenal catecholamines and beta-adrenoceptors
Neuroimmunomodulation
Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape
Nat Med
A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases
Cancer
Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis
Proc Natl Acad Sci U S A
Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer
J Clin Invest
Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients
J Clin Oncol
A pooled analysis of bone marrow micrometastasis in breast cancer
N Engl J Med
CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells
Stem Cells
Promotion of prostatic metastatic migration towards human bone marrow stoma by omega − 6 and its inhibition by omega − 3 PUFAs
Br J Cancer
Osteoblastic cells regulate the haematopoietic stem cell niche
Nature
A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer
Cancer
PDGFR signaling blockade in marrow stroma impairs lung cancer bone metastasis
Cancer Res
Dissemination and growth of cancer cells in metastatic sites
Nat Rev Cancer
Osteopontin increases migration and MMP-9 up-regulation via αvβ3 integrin, FAK, ERK, and NF-κB-dependent pathway in human chondrosarcoma cells
J Cell Physiol
Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis
Proc Natl Acad Sci U S A
Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation
N Engl J Med
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