Associate editor: B. Teicher
Targeting tumor–stromal interactions in bone metastasis

https://doi.org/10.1016/j.pharmthera.2013.10.006Get rights and content

Abstract

Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor–stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating 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)

  • B. Eibl et al.

    Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer

    Blood

    (1996)
  • O.V. Glinskii et al.

    Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-l-leucine

    Neoplasia

    (2012)
  • C.L. Hall et al.

    Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase

    Neoplasia

    (2008)
  • P.V. Hauschka et al.

    Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose

    J Biol Chem

    (1986)
  • J. Heimburg et al.

    Inhibition of spontaneous breast cancer metastasis by anti-Thomsen–Friedenreich antigen monoclonal antibody JAA-F11

    Neoplasia

    (2006)
  • A. Hercbergs et al.

    Reduced thoracic vertebrae metastases following post mastectomy parasternal irradiation

    Int J Radiat Oncol Biol Phys

    (1985)
  • Y. Hüsemann et al.

    Systemic spread is an early step in breast cancer

    Cancer Cell

    (2008)
  • M. Iwamura et al.

    Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen

    Urology

    (1996)
  • Y. Kang et al.

    Tumor cell dissemination: Emerging biological insights from animal models and cancer patients

    Cancer Cell

    (2013)
  • Y. Kang et al.

    A multigenic program mediating breast cancer metastasis to bone

    Cancer Cell

    (2003)
  • Y. Katayama et al.

    PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: Evidence for cooperation between E-selectin ligands and alpha4 integrin

    Blood

    (2003)
  • M. Labelle et al.

    Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis

    Cancer Cell

    (2011)
  • D.L. Lacey et al.

    Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation

    Cell

    (1998)
  • G.B. Adams et al.

    Therapeutic targeting of a stem cell niche

    Nat Biotechnol

    (2007)
  • J.A. Aguirre Ghiso et al.

    Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling

    J Cell Biol

    (1999)
  • J.A. Aguirre-Ghiso

    Models, mechanisms and clinical evidence for cancer dormancy

    Nat Rev Cancer

    (2007)
  • J. Akech et al.

    Runx2 association with progression of prostate cancer in patients: Mechanisms mediating bone osteolysis and osteoblastic metastatic lesions

    Oncogene

    (2010)
  • M.A. Bagshaw et al.

    Radiation treatment of prostate bone metastases and the biological considerations

    Adv Exp Med Biol

    (1992)
  • S.J. Bakewell et al.

    Platelet and osteoclast beta3 integrins are critical for bone metastasis

    Proc Natl Acad Sci U S A

    (2003)
  • S. Bandyopadhyay et al.

    Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression

    Nat Med

    (2006)
  • S.K. Baniwal et al.

    Runx2 transcriptome of prostate cancer cells: Insights into invasiveness and bone metastasis

    Mol Cancer

    (2010)
  • M. Banys et al.

    Hematogenous and lymphatic tumor cell dissemination may be detected in patients diagnosed with ductal carcinoma in situ of the breast

    Breast Cancer Res Treat

    (2011)
  • G.L. Barnes et al.

    Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells

    Cancer Res

    (2003)
  • S.R. Barthel et al.

    Definition of molecular determinants of prostate cancer cell bone extravasation

    Cancer Res

    (2013)
  • S. Ben-Eliyahu et al.

    Suppression of NK cell activity and of resistance to metastasis by stress: A role for adrenal catecholamines and beta-adrenoceptors

    Neuroimmunomodulation

    (2000)
  • B.N. Bidwell et al.

    Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape

    Nat Med

    (2012)
  • J.J. Body et al.

    A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases

    Cancer

    (2003)
  • L. Borsig et al.

    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

    (2002)
  • A. Boucharaba et al.

    Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer

    J Clin Invest

    (2004)
  • S. Braun et al.

    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

    (2000)
  • S. Braun et al.

    A pooled analysis of bone marrow micrometastasis in breast cancer

    N Engl J Med

    (2005)
  • S. Brenner et al.

    CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells

    Stem Cells

    (2004)
  • M.D. Brown et al.

    Promotion of prostatic metastatic migration towards human bone marrow stoma by omega  6 and its inhibition by omega  3 PUFAs

    Br J Cancer

    (2006)
  • L.M. Calvi et al.

    Osteoblastic cells regulate the haematopoietic stem cell niche

    Nature

    (2003)
  • M.A. Carducci et al.

    A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer

    Cancer

    (2007)
  • R. Catena et al.

    PDGFR signaling blockade in marrow stroma impairs lung cancer bone metastasis

    Cancer Res

    (2010)
  • A.F. Chambers et al.

    Dissemination and growth of cancer cells in metastatic sites

    Nat Rev Cancer

    (2002)
  • Y.-J. Chen et al.

    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

    (2009)
  • M.L. Cher et al.

    Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis

    Proc Natl Acad Sci U S A

    (2003)
  • R. Childs et al.

    Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation

    N Engl J Med

    (2000)
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