Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner

2019

JBMR Plus

Bone marrow provides a unique microenvironment favoring the colonization and outgrowth of metastatic tumor cells. Despite the high incidence of bone metastasis in breast and prostate cancer patients, many of the molecular mechanisms controlling metastatic progression remain unclear. Several gene signatures associated with bone metastasis have been reported, but no metastasis‐specific gene alterations have been identified. Therefore, there has been considerable interest in understanding how the bone microenvironment impacts the behavior of disseminated tumor cells (DTCs) prior to and following colonization of the bone. Substantial evidence indicates that disruption of normal bone homeostasis by tumor‐derived factors establishes a premetastatic niche within the bone that favors DTC colonization. Following dissemination, bone resident cells and the surrounding stroma provide critical signals that support tumor cell colonization, survival, and eventual outgrowth. Clinical data suggest that patients can harbor DTCs for years to decades prior to developing overt bone metastases, suggesting a period of tumor dormancy occurs in the bone marrow. Several dormancy‐promoting factors have been recently identified; however, critical questions surrounding the molecular triggers and timing of tumor cell emergence from dormancy remain. Here, we review how metastatic tumor cells co‐opt the bone marrow microenvironment for metastatic progression and discuss emerging insights into how to more effectively target DTCs and prevent metastasis. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Section: Metastatic Outgrowthmentioning

confidence: 99%

Bone as a Preferential Site for Metastasis

Sowder

2019

JBMR Plus

“…PTHrP was originally discovered as the factor that causes humoral hypercalcemia of malignancy and is well established to promote tumor‐induced bone destruction through its stimulation of RANKL on osteoblast lineage cells to promote osteoclast‐mediated bone resorption . More recently, it has been suggested that PTHrP may also play a role in the awakening of tumor cells in the bone marrow . Overexpression of PTHrP, which normally binds to the parathyroid hormone receptor type 1 (PTHR1) to induce cAMP signaling, induces osteolytic bone destruction in cells that otherwise lie dormant in the bone marrow and down‐regulates a number of pro‐dormancy genes through a cAMP‐independent mechanism .…”

Section: Factors Controlling Dormancy or Reactivationmentioning

confidence: 99%

“…More recently, it has been suggested that PTHrP may also play a role in the awakening of tumor cells in the bone marrow . Overexpression of PTHrP, which normally binds to the parathyroid hormone receptor type 1 (PTHR1) to induce cAMP signaling, induces osteolytic bone destruction in cells that otherwise lie dormant in the bone marrow and down‐regulates a number of pro‐dormancy genes through a cAMP‐independent mechanism . Interestingly, PTHrP is regulated by the bone matrix itself, in that tumor cells that come in contact with the rigid bone surface up‐regulate PTHrP; however, this is specific for tumor cells that are already aggressive in nature .…”

Section: Factors Controlling Dormancy or Reactivationmentioning

confidence: 99%

“…While new models such as these are in development, the most common models to study tumor dormancy in bone are intratibial and intracardiac injections into various mouse strains . These injection types are more commonly used to investigate tumor dormancy in bone than orthotopic injections into the primary tumor site, since intratibial and intracardiac innoculations allow the delivery of sufficient numbers of cells to the bone marrow, making the detection of the tumor cells in the bone more feasible .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tumor dormancy in bone

Mayhew¹,

Omokehinde²,

2019

Cancer Reports

Self Cite

Background Bone marrow is a common site of metastasis for a number of tumor types, including breast, prostate, and lung cancer, but the mechanisms controlling tumor dormancy in bone are poorly understood. In breast cancer, while advances in drug development, screening practices, and surgical techniques have dramatically improved survival rates in recent decades, metastatic recurrence in the bone remains common and can develop years or decades after elimination of the primary tumor. Recent Findings It is now understood that tumor cells disseminate to distant metastatic sites at early stages of tumor progression, leaving cancer survivors at a high risk of recurrence. This review will discuss mechanisms of bone lesion development and current theories of how dormant cancer cells behave in bone, as well as a number of processes suspected to be involved in the maintenance of and exit from dormancy in the bone microenvironment. Conclusions The bone is a complex microenvironment with a multitude of cell types and processes. Many of these factors, including angiogenesis, immune surveillance, and hypoxia, are thought to regulate tumor cell entry and exit from dormancy in different bone marrow niches.

“…Bone-DTCs secrete factors (e.g., parathyroid-hormone-related protein (PTHrP)) that stimulate the receptor activator of NF-κB (RANK)-RANK ligand (RANKL) axis and promote osteoclastogenesis [4]. These factors may enable tumor cells to overcome quiescence [5], but it remains unclear whether some breast cancer cells begin secreting these factors prior to dissemination or during circulation, or whether the bone microenvironment induces breast cancer cells to stimulate osteoclasts. Increased osteoclastogenesis gives rise to localized bone resorption and the release of cytokines and growth factors from the bone matrix that stimulate tumor cell growth and further enhance the RANK-RANKL signaling cascade to promote bone resorption [4], resulting in overt tumor-induced bone disease.…”

Section: Introductionmentioning

confidence: 99%

GP130 Cytokines in Breast Cancer and Bone

Omokehinde

2020

Cancers

Self Cite

Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.