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Keywords:

  • bone metastases;
  • breast carcinoma;
  • osteolysis;
  • osteoclasts;
  • PTHrP;
  • TGFβ

Abstract

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

Osteolytic and osteoblastic metastases are often the cause of considerable morbidity in patients with advanced prostate and breast carcinoma. Breast carcinoma metastasis to bone occurs because bone provides a favorable site for aggressive behavior of metastatic cancer cells. A vicious cycle arises between cancer cells and the bone microenvironment, which is mediated by the production of growth factors such as transforming growth factor β and insulin growth factor from bone and parathyroid hormone-related protein (PTHrP) produced by tumor cells. Osteolysis and tumor cell accumulation can be interrupted by inhibiting any of these limbs of the vicious cycle. For example, bisphosphonates (e.g., pamidronate, ibandronate, risedronate, clodronate, and zoledronate) inhibit both bone lesions and tumor cell burden in bone in experimental models of breast carcinomametastasis. Neutralizing antibodies to PTHrP, which inhibit PTHrP effects on osteoclastic bone resorption, also reduce osteolytic bone lesions and tumor burden in bone. Other pharmacologic approaches to inhibit PTHrP produced by breast carcinoma cells in the bone microenvironment also produce similar beneficial effects. Identification of the molecular mechanisms responsible for osteolytic metastases is crucial in designing effective therapy for this devastating complication. Cancer 2003;97(3 Suppl):834–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11132

There have been considerable improvements in our understanding of the mechanisms by which solid tumors such as breast and prostate carcinoma affect the skeleton, as well as major improvements in our understanding of the cellular mechanisms and mediators responsible for bone destruction in patients with myeloma bone disease. This has occurred in parallel with new treatment approaches specifically designed to ameliorate the skeletal complications of malignancy. This is a particularly exciting time to work in this area, and this is reflected by a number of recent national and international conferences on cancer-induced bone diseases.

SOLID TUMORS AND BONE METASTASIS

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

The skeleton is one of the most favored sites for metastasis of solid tumors. Bone metastasis is a catastrophic complication for most patients, although in the early stages it may be occult and inapparent. The malignant process is incurable and results in intractable pain and other local complications such as fracture after trivial injury and nerve compression. Extensive bone destruction can lead to hypercalcemia, the most rapidly fatal complication.

CLASSIFICATION OF BONE METASTASES

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

Tumors cause two distinct (but overlapping) types of skeletal lesions when they spread to bone. The most common form of bone metastasis is the destructive osteolytic lesion. In this type of metastatic bone lesion, tumor products distort the normal remodeling sequence so that there is an increase primarily in osteoclast activity and subsequent bone destruction. The secondary osteoblast response seen in normal bone remodeling is almost always impaired, so that the lesion is predominantly lytic. Less common is the predominantly osteoblastic response that occurs without previous resorption at the same site. The mechanisms responsible for tumors causing distinctive and discrete effects on osteoblasts and osteoclasts involved in normal bone remodeling remain obscure, although recent information is providing some clarification.

FREQUENCY OF BONE METASTASES

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

The most common malignant tumors that involve the skeleton. According to the American Cancer Society, 553,400 cancer deaths are expected to occur in the United States in 2001 and at least two-thirds of these had bone metastases. Almost 200,000 people will die with lung and breast carcinoma and the frequency of bone metastases in these patients is even greater. Although bone metastasis occurs frequently with nearly all tumors, some cancers (e.g., breast and prostate carcinoma) have a special predilection for the skeleton.

However, these estimates of the frequency of metastasis depend on the sensitivity of the diagnostic technique utilized to detect them. The most commonly used techniques are bone scans, X-rays, and histologic evaluation of autopsy specimens. Both radiologic and histologic assessments are limited by the extent of the sample evaluated. Bone scans survey the whole body. However, because isotope accumulation depends on osteoblast activity, lesions with very little osteoblastic component cannot be detected. Estimates of metastasis may also depend on the length of time the patient lives. For example, patients with disseminated breast carcinoma may live longer and are more likely to develop bone metastases than patients with lung carcinoma who have a much shorter life expectancy. Evaluation of biochemical markers of bone metabolism may be helpful in detecting bone metastases and in monitoring treatment.1, 2 Skeletal involvement is also common in some patients with hematologic malignancies, most notably patients with myeloma. Myeloma almost always causes osteolytic lesions, which are present in at least 80% of cases.3 Both osteolytic and osteoblastic lesions can occur in patients with lymphomas, particularly Hodgkin disease, but these are not as common as they are in patients with myeloma. In a small percentage of patients with myeloma, osteosclerosis occurs due to a generalized stimulation of osteoblast activity.

Tumor cells most frequently affect the heavily vascularized areas of the skeleton, particularly the red bone marrow of the axial skeleton and the proximal ends of the long bones, the ribs, and the vertebral column. This is true for hematologic malignancies and for all solid tumors. Although metastases to the appendicular skeleton occur less frequently, they may be seen particularly in patients with melanoma and renal carcinoma. Breast carcinoma cells sometimes metastasize to the posterior clinoid processes. The precise reasons for these unusual distributions of bone lesions are not clear.

PATHOPHYSIOLOGY OF THE METASTATIC PROCESS

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

The metastasis of tumor cells to specific sites in the skeleton is not a simple and random event determined solely by blood flow. Rather, it is a directed and multistep process that is dependent on specific properties of the tumor cells and on factors in the bone microenvironment that favor metastasis. Liotta and Kohn4 suggested that although the distribution of metastases in distant organs can be predicted by the anatomic distribution of blood flow from the primary site in 30% of cases, specific properties of the tumor cell and features at the metastatic site determine where the metastasis occurs in the majority of cases. More than 100 years ago, this nonrandom concept for tumor metastasis was recognized by Paget,5 who used the term “seed and soil” to explain the phenomenon of tumor spread to specific sites in the body.

Because tumor metastasis is a multistep process involving separate discrete steps, interruption of one or more of these steps can inhibit the metastatic process. Each of these discrete steps represents cellular interactions caused by specific determinants of both the tumor and the tissue.4, 6 The steps involved in the shedding of tumor cells from the primary site involve detachment of tumor cells from adjacent cells, followed by invasion of adjacent tissue in the primary organs. The cells then enter tumor capillaries (stimulated by specific angiogenesis factors produced by the tumor) and via these capillaries reach the general circulation.7 The steps involved in entering the tumor blood vessels at the primary site are similar to those involved in exiting the vasculature in the bone marrow cavity. These steps include the attachment of the tumor cells to basement membrane, the secretion of proteolytic enzymes that enable tumor cells to disrupt the basement membrane, and the migration of the tumor cells through the basement membrane.4, 8, 9

TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

Although definitive proof is still not available to explain the cellular mechanism responsible for local destruction of bone by tumor cells, it is likely that the predominant mechanism for bone destruction is an increase in osteoclast activity. In other words, tumors produce local factors that stimulate osteoclasts, which, in turn, are responsible for the resorption of bone. The alternative possibility is that tumor cells may destroy bone directly without the addition of osteoclasts. Two pieces of evidence support the view that osteoclastic bone resorption is the predominant mechanism. First, scanning electron microscopy studies invariably detect osteoclasts adjacent to tumor deposits.10 Moreover, distinctive osteoclast resorption lacunae are universally present. Such studies show no evidence of smaller resorption lacunae corresponding to the size of the tumor cells. Second, drugs that inhibit osteoclast activity (e.g., bisphosphonates, plicamycin, and gallium nitrate) also reduce hypercalcemia, which is due predominantly to increased bone resorption caused by tumors. As a result, these drugs decrease the morbidity from breast carcinoma metastases to bone. These data suggest that osteoclasts are the major (and, possibly, the sole) mediators of the bone destruction. Nevertheless, there is in vitro evidence that suggests that breast carcinoma cells have the capacity to cause bone resorption in vitro. When breast carcinoma cells were added to devitalized bone, they caused both mineral release and matrix degradation.11

MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

The major cellular mechanism for bone destruction in osteolytic bone disease is osteoclastic. Consequently, there is interest in determining the mediator responsible for this increase in osteoclast activity. Previous studies suggested that the tumor peptide, parathyroid hormone-related protein (PTHrP), is associated with humoral hypercalcemia of malignancy.12 Even though many of these patients do not have increased plasma PTHrP or increased nephrogenous cyclic adenosine monophosphte, the absence of these parameters does not mean that PTHrP is unimportant. Immunohistochemistry studies have shown increased expression of PTHrP in bone sites compared with either soft tissue metastases or primary tumors in patients with carcinoma of the breast.13, 14 We have studied the human breast carcinoma cell line, MDA-MB-231. Nude mice inoculated with this cell line developed osteolytic lesions 4–6 weeks later. We and others15 have found that there is an increase in PTHrP expression in the human breast cancer cells innoculated into mice that metastasize to bone, similar to the conditions described in patients.13 This is also associated with the development of typical osteolytic bone lesions seen in patients with the disease. When tumor-bearing nude mice are treated with neutralizing antibodies to PTHrP, not only is there a decrease in the development of the osteolytic bone lesions, there is also a decrease in the tumor burden in bone.16 Miki et al.17 reported a clear correlation between PTHrP production by human small-cell lung carcinoma cells and development of bone metastases in mice. The most likely explanation for the increase in PTHrP production in the bone microenvironment is that bone provides a fertile environment for the growth of tumor cells and enhances the production of PTHrP. Others have shown that a likely mechanism responsible for this effect is the production of transforming growth factor β (TGFβ), which is released from bone in active form when bone resorbs.18 MDA-MB-231 cells that express a dominant-negative Type II TGFβ receptor are unresponsive to TGFβ;. As a result, the progression of osteolytic bone lesions is significantly slowed compared with metastasis caused by parental MDA-MB-231 cells.19 The overexpression of the constitutively active Type I TGFβ receptor in MDA-MB-231 cells increased tumor burden and osteolytic lesions in mice.19 The tumor-bearing mice treated with PTHrP antibodies had significantly lower tumor burdens than the mice treated with a control antibody.20 These studies demonstrate that TGFβ is a critical mediator of breast carcinoma-mediated osteolytic metastasis and that the effector of this response is PTHrP.

Transforming growth factor β signals through various pathways. Although the intracellular mediators of TGFβ, i.e., Smads, are indispensable for many of the responses to TGFβ,21–23 there is also accumulating evidence that TGFβ signals through other pathways.24, 25 Käkönen et al.20 showed that stable transfection of wild-type Smads 2, 3, or 4 increased TGFβ-stimulated PTHrP secretion in MDA-MB-231 cells, whereas dominant-negative Smads 2, 3, or 4 only partially reduced this effect. Because these results suggested that the TGFβ stimulation of PTHrP was both Smad dependent and Smad independent, the role of other signaling pathways was determined. When the cells were treated with a variety of protein kinase inhibitors, specific inhibitors of the p38 MAP kinase pathway significantly reduced TGFβ-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 mitrogen-activated protein kinase (MAP) kinase inhibition completely inhibited TGFβ-stimulated PTHrP production in MDA-MB-231 cells. Käkönen et al.26 also studied the effect of p38 MAPK inhibitors on osteolytic cancer cell lines other than MDA-MB-231. They observed a significant or complete inhibition of TGFβ-induced PTHrP secretion by the cells. Therefore, the p38 MAP kinase pathway may be a major component of Smad-independent signaling by TGFβ to increase tumor PTHrP production and it may provide a new molecular target for antiosteolytic therapy.

Metastatic cancer cells in the bone microenvironment secrete PTHrP and stimulate osteoclastic bone resorption. This is accomplished by increasing osteoblastic expression of the cell membrane-associated protein termed “receptor activator of NF-κB ligand” (RANKL). The RANKL binds to its receptor RANK, which is expressed on osteoclasts. It enhances the differentiation and fusion of active osteoclasts in the presence of macrophage–colony-stimulating factor.27, 28 Concomitantly, the production of a soluble decoy receptor for RANKL, osteoprotegerin, by osteoblastic stromal cells is down-regulated.27, 29 Figure 1 shows the destructive vicious cycle between the tumor-produced PTHrP and the bone-derived TGFβ.

thumbnail image

Figure 1. The cycle in osteolytic bone metastases. Tumor cells in bone secrete parathyroid hormone-related protein (PTHrP), which stimulates osteoclastic bone resorption via receptor activator NF-κB ligand (RANKL) produced by osteoblasts. Concomitantly, the production of osteoprotegerin (OPG), a soluble decoy receptor for RANKL, is down-regulated. Transforming growth factor β (TGFβ) released during osteoclastic bone resorption increases tumor production of PTHrP via TGFβ receptors and Smad and p38 MAP kinase pathways. This interaction between tumor cells and bone results in bone destruction associated with breast carcinoma.

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Tumor cells may release soluble mediators other than PTHrP that act either on osteoblastic stromal cells to enhance the production of osteoclast-activating factors or on osteoclasts. Interleukin (IL)-11, an IL-6 family cytokine, is produced by a variety of stromal cells including fibroblasts, epithelial cells, and osteoblasts and has pleiotropic effects on a variety of tissues.30 It enhances bone resorption by promoting osteoclastogenesis31 and suppressing the activity of osteoblasts.32 In addition, osteolytic cancer cells produce IL-11 by themselves or by indirectly stimulating its production from osteoblasts.33–35 Production of IL-11 in human osteosarcoma and breast carcinoma cells is increased by TGFβ1 and PTHrP.33, 34, 36, 37 In line with these in vitro reports, overexpression of IL-11 in MDA-MB-231 breast carcinoma cells increases the tumor burden and osteolytic lesions in vivo using a mouse model of bone metastases.38 Expression of soluble RANKL by tumor cells has been reported,39 although most osteolytic cancer cell lines studied so far do not express RANKL.30, 40

Matrix metalloproteinases (MMPs) also play a role in the removal of surface collagenous osteoids before the attachment of osteoclasts and are therefore also likely to play a role in tumor-mediated osteolysis. Inhibition of MMPs reduces tumour burden and osteolysis in animal models of bone metastases.41, 42

Although TGFβ is crucial for the development and progression of bone metastases, it is probably not the only bone-derived growth factor involved in this process. It is also likely that there are other mechanisms for bone destruction associated with tumor cells that metastasize to bone. These may involve tumor cell or host immune cell products in the bone microenvironment of mediators such as TGFα, IL-1β, tumor necrosis factor, IL-6, and vascular endothelial growth factor. Most of these factors stimulate osteoclastic bone resorption and enhance the osteoclast-stimulating activity of PTHrP.43–45 In addition, high calcium concentration at sites of osteolysis may increase tumor secretion of PTHrP.46, 47

BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES

Bone provides a favorable niche for tumor cells because it is a large repository or storehouse for growth regulatory factors.48 In addition to its rich stores of TGFβ, bone contians other growth regulatory factors that may act as tumor growth factors including bone morphogenetic proteins, heparin-binding fibroblast growth factors, platelet-derived growth factors, and insulin-like growth factors I (IGF-1) and II. These factors are presumably the reason that bone is resorbed so avidly in metastases. They may be made available locally through bone resorption. This has been shown particularly in the case of TGFβ, which may alter the behavior of many tumor cells, particularly breast carcinoma cells, to enhance the production of PTHrP.49–51

To conclude, the mechanisms responsible for osteolysis in bone metastases involve complex interactions between the tumor cells and bone. Bone-derived growth factors (e.g., TGFβ) released during osteoclastic bone resorption increase tumor production of osteolytic factors such as PTHrP. These factors produced by tumor cells in turn increase osteolysis by stimulating osteoclast function directly or indirectly via other bone marrow cells. Increased osteolysis releases more growth factors near the tumor site and a destructive vicious cycle between tumor cells and bone forms. Transforming growth factor β and PTHrP are not the only participants in this vicious cycle destructive to bone. Other bone-derived growth factors, such as IGF-1, may also participate in the vicious cycle by stimulating tumor growth in bone. Moreover, tumor cells also produce other factors that stimulate osteoclast function, such as IL-11 and VEGF, and their production in breast carcinoma cells is increased by TGFβ. To optimize the reduction in osteolysis and tumor burden in bone, we need more information on all of the cellular and molecular mechanisms involved in this cycle. Focusing on finding targets to inhibit the function of this cycle should lead to more effective therapy for this devastating complication of cancer.

REFERENCES

  1. Top of page
  2. Abstract
  3. SOLID TUMORS AND BONE METASTASIS
  4. CLASSIFICATION OF BONE METASTASES
  5. FREQUENCY OF BONE METASTASES
  6. PATHOPHYSIOLOGY OF THE METASTATIC PROCESS
  7. TUMOR CELL MEDIATION OF BONE DESTRUCTION AT THE METASTATIC SITE
  8. MECHANISMS OF OSTEOCLAST STIMULATION AT THE METASTATIC SITE
  9. BONE-DERIVED TUMOR GROWTH FACTORS AT THE METASTATIC SITE
  10. Acknowledgements
  11. REFERENCES
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