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Physiopathology of Spine Metastasis

Physiopathology of Spine Metastasis Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 107969, 8 pages doi:10.1155/2011/107969 Review Article 1 1 2 1 Giulio Maccauro, Maria Silvia Spinelli, Sigismondo Mauro, Carlo Perisano, 1 2 Calogero Graci, and Michele Attilio Rosa Department of Orthopaedics and Traumatology, Agostino Gemelli Hospital, Catholic University, L.go F. Vito, 1-00168 Rome, Italy Department of Orthopaedics, Messina University, Via Consolare Valeria, 1-98122 Messina, Italy Correspondence should be addressed to Giulio Maccauro, giuliomac@tiscali.it Received 7 February 2011; Accepted 1 June 2011 Academic Editor: Alessandro Gasbarrini Copyright © 2011 Giulio Maccauro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The metastasis is the spread of cancer from one part of the body to another. Two-thirds of patients with cancer will develop bone metastasis. Breast, prostate and lung cancer are responsible for more than 80% of cases of metastatic bone disease. The spine is the most common site of bone metastasis. A spinal metastasis may cause pain, instability and neurological injuries. The diffusion through Batson venous system is the principal process of spinal metastasis, but the dissemination is possible also through arterial and lymphatic system or by contiguity. Once cancer cells have invaded the bone, they produce growth factors that stimulate osteoblastic or osteolytic activity resulting in bone remodeling with release of other growth factors that lead to a vicious cycle of bone destruction and growth of local tumour. 1. Introduction who will die of cancer in 2010, almost all will have metastasis to some part of the body. It is estimated that about 350,000 The metastasis is the spread of cancer from one part, where people die with bone metastasis each year in the United States it started (called its primary site) of the body to another. [5]. Sometimes bone metastasis is not clinically visible and A tumour formed by cells that have spread is called a their demonstration occurs during autopsy; therefore, the “metastatic tumour” or a “metastasis.” The metastatic tum- real incidence of bone metastasis is not possible to report our contains cells that are like those in the original (primary) [6]. Bone metastasis is actually much more common than tumour [1]. When cells break away from a cancerous tumour, primary bone cancers [2, 7] because the incidence is 25/1 they can travel to other areas of the body through the and they are the neoplastic lesions more seen by orthopedist bloodstream or lymph system. From there, they can end up [8, 9]. Bones are the most common place for metastasis in any organ or tissue. Many of the cancer cells that break off after lung and liver [2, 3, 10]. Primary tumors that most from the original tumour die without causing any problems. often leads to bone metastasis are in the order of incidence: Some, however, settle in a new area. There, they begin to prostate, breast, kidney, lung, and thyroid cancer [6]. The grow and form new tumours. Sometimes metastatic tumours incidence of skeletal metastasis from autopsy studies is of are found by tests that are done when the primary cancer is 73% (range of 47–85%) in the breast cancer, 68% (range first diagnosed. In other cases, the metastasis is found first, of 33–85%) in the prostate cancer, 42% (range of 28–60%) causing the doctor to look for the place that the cancer started in the thyroid cancer, 36% (range of 30–55%) in the lung [2, 3]. cancer, 35% (range of 33–40%) in the kidney cancer, 6% (range of of 5–7%) in the esophageal cancer, 5% (range of 3–11%) in the gastrointestinal tract cancers, 11% (range of 2. Epidemiology 8–13%) in the rectal cancer [11]. Given the high prevalence Approximately two-thirds of patients with cancer will of breast, prostate, and lung cancer, they are responsible for develop bone metastasis [4]. Of the estimated 569,490 people more than 80% of cases of metastatic bone disease [12]. 2 International Journal of Surgical Oncology According to Roodman GD, up to 70% of patients with your usual activities and lifestyle [2]. A spinal metastasis may breast cancer or prostate cancer, and 15 to 30% of patients cause pain, instability, neurological injuries with loss of con- with lung, colon, bladder, or kidney cancer develop bone trol urinary and rectal sphincter up to paraplegia. However, metastasis [13]. Breast cancer is the most common malignant 60% of all bone metastasis [26] and 36% of vertebral lesions tumour and the main cause of bone metastasis in women [27] are asymptomatic and discovered occasionally. Symp- [14]. About 70% of people who die from breast cancer will tomatic spinal cord involvement occurs in 18 000 patients per have radiological evidence of skeletal metastasis before their year [18]. Brihaye et al. analyzed 1477 cases concluded that death and in 40% of cases the bone is the first metastatic 16.5% of spinal metastases with epidural involvement came site [11]; the estrogen receptors [11], the sialoprotein [15], from the breast cancer, 15.6% from the lung cancer, 9.2% the parathyroid-related peptide (PTHrP) [16], and 69 gene from prostate cancer, and 6.5% from kidney cancer; they also signature correlated with fibroblasts growth factors [17]are analyzed 1585 cases of symptomatic epidural metastases and predictive markers of bone recurrence [12]. While prostate reported that 70.3% had involvement of thoracic and thora- and lung metastasis are those that occur more in men [14]. columbar region, 21.6% of the lumbar and sacral region, and The primary tumor cannot be determined in 9% of cases of 8.1% of the cervical and cervical-thoraco region, concluding spinal metastases [18]. that although the lumbar region is more involved, the ma- jority of patients with neurological dysfunction have thoracic lesions [28]. 3. Locations of Spine Metastasis Metastasis can occur in any bone in the body but is most 5. Prognosis often found in bones near the center of the body. The spine is the most common site of bone metastasis [2, 12]. It is esti- Once cancer has spread to the bones or to other sites in mated that over the 10% of patients with cancer will develop the body, it is rarely able to be cured, but often it can still a symptomatic spinal metastasis [19, 20]. Algra et al. suggest be treated to shrink, stop, or slow its growth. Even if cure that the initial anatomic location of metastases within is no longer possible, treating the cancer may be able to vertebrae is in the posterior portion of the body. Analysis of help you live longer and feel better [2]. The diagnosis of CT scans shows that the body is involved before the pedicles, metastasis changes the patients’ prognosis; according to data although destruction of the pedicles is the most common from the ACS, the survival rate at five years in nonmetastatic finding on plain films. Destruction of the pedicles occurs carcinomas treated from 1996 to 2002 was of 100% in only in combination with the involvement of the vertebral prostate cancer, 97% in the thyroid cancer, 89% in the breast body [21]. Other common sites are the hip bone (pelvis), cancer, 66% in the kidney cancer, and 16% in the lung cancer; upper leg bone (femur), upper arm bone (humerus), ribs, in the same period, in the metastatic tumors at presentation, and the skull [2, 14]. Studies showed that the thoracic spine the five-year survival rate was of 56% in thyroid cancer, 33% is the region more involved with metastasis [22], while others in prostate cancer, 26% in breast cancer, 10% in renal cancer, studies highlighted how the lumbar spine is more involved and 2% in lung cancer [29]. [23, 24]. The cervical spine is the least involved (10%) [14]. More than 50% of patients with spinal metastasis have 6. Method of Dissemination multiple levels involved, and 10 to 38% of patients have multiple, noncontiguous segments involved [14]. The lung The cancer can metastasize in the bone through different and breast cancers metastasize preferably in the thoracic ways of propagation: the most frequent is the hematogenous region because the venous drainage of the breast through way, the intravenous one for lesions of the spinal column, the azygos communicates with the plexus of Batson in the and the arterial one for lesions that at the beginning are prox- thoracic region [21, 23, 25], while lung cancer drains through imal (shoulder and pelvis) and then distal (elbow and knee). the pulmonary veins in the left heart and from there is Less frequent lesions are those ones by contiguity and even distributed in the generalized manner in the skeletal; prostate less frequent are those ones for lymphatic spread (whose role cancer metastasizes usually to the lumbar-sacral spine and is not well defined) [6, 14]. The diffusion through the venous pelvis, because it drains through the pelvic plexus in the lum- system is the principal process of spinal metastasis. In 1940, bar region [25]. Colon and rectal tumors usually metastasize Batson (Figure 1) demonstrated by injecting contrast into through the portal system in the liver and lung, and only late the vein of the penis in males and into the veins of the breast in skeletal [14]. in women that the contrast and so the tumor cells spread in the blood into the spinal veins as a result of venous reflux that occurred after an increase of intrathoracic pressure and/or 4. Symptoms of Bones and Spine Metastasis intra-abdominal as for a Valsalva maneuver [30]. It was an Bone metastasis is one of the most frequent causes of pain in explanation of the possibility of the diffusion of breast cancer people with cancer. When a cancer spreads to the bone, it can in the column that is drained mainly by the azygos vein make the bones weaker and even cause them to break without which communicates with the paravertebral venous plexus an injury [2, 7]. As the cancer cells damage the bones, of Batson in the thoracic region and prostate cancer that is calcium is released into the blood. This can lead to problems drained from the venous plexus which communicates with from high blood calcium levels. Bone metastasis can also the pelvic plexus of Batson at the lumbar [31]. This hypoth- cause other problems that can limit your ability to keep up esis was confirmed by the study of Coman and DeLong, who International Journal of Surgical Oncology 3 (a) (b) Figure 1: Batson venous plexus, from Batson O.V., “The function of the vertebral veins and their role in the spread of metastases,” Ann Surg. 1940 July; 112 (1): 138–149. noted that lumbar spinal tumor metastasis appeared in 70% normal conditions deviate 5–10% of blood in the vertebral of the animals, injecting cancer cells into the femoral vein venous system and with the latter [14, 23, 30, 33, 34]. Cancer of rats, when an external abdominal pressure was carried cells may metastasize through the blood system and into the out [23, 32]. The venous plexus of Batson is a system of vertebral body directly through the nutrient arteries as in the veins located in the epidural space between the spinal column case of lung cancer [14, 35]. Arguello et al. showed that the bone and the dura mater, with no valves that control the injection of a variety of tumor cells into the systems arterial flow of blood, so that each increase of pressure in the system circulation of mice resulted in a syndrome of tumor coloniza- of the vena cava results in an increased flow level of the tion of the vertebra followed by a spinal cord compression plexus. It is connected to the portal and caval system that in [36]. The direct diffusion of prostate cancer at the lumbar 4 International Journal of Surgical Oncology spine and the direct diffusion of the breast and lung ones at to clinically manifest metastases depends on a number of the thoracic spine are other methods of spreading [14]. promoting or inhibiting conditions, primarily on interaction with surrounding bone and bone marrow cells, through the increased expression of adhesion molecules, the availability 7. Mechanism of Localization of of space, degree of vascularity, and type of bone remodelling. Metastases in Bone The development of a metastasis obviously depends on The development of a bone metastasis is not a simple process the proliferation of neoplastic cells, but other processes are of transport, arrest, and growth of cancer cells in these critical in this connection, primarily neo-angiogenesis [69]. spaces. Before moving to the bone marrow and taking root and growing in its spaces, neoplastic cells have to follow a 8. Pathogenesis long route [37]. They must first spread through the primary site at the expense of the preexisting cells and stroma then The bone tissue undergoes a continuous process of resorp- detach from it by the reduction of adhesion molecules and tion by the action of osteoclasts, and remodelling, through the opening of the epithelial basal lamina, afterwards reach the action of osteoblasts. In normal individuals, this process the blood vessels and penetrate into them by degradation is balanced. In cancer cells, this balance is lost and lytic, thick- of their basal lamina and endothelium, then migrate with ener, or mixed lesions are created [12, 13]. The osteolytic lesions are caused by stimulation of osteoclastic activity the bloodstream and escape the surveillance of the immune cells, reach the bone marrow sinusoids, stop and grow there accompanied by reduced osteoblastic activity not by direct [38, 39]. These processes mainly occur through the activity effects of tumour cells on the bone [70, 71]. The osteoblastic of proteinases, such as the metalloproteinases, the serine, lesions are expression of an increased bone formation around cysteine, and aspartic proteinases [40–53], stromelysin [54], the tumour cells associated with a disequilibrium of the uPA [55, 56]. These proteinases destroy the epithelial basal osteolytic activity and with an altered turnover of the bone lamina and the surrounding tissue by degradation of type [71]. Once cancer cells have invaded the bone, they produce IV collagen, laminin, proteoglycans, and other proteins but growth factors that directly stimulate osteoclastic activity and/or osteoblastic activity resulting in bone remodelling also uncover hidden biologic activities and reduce cell-to-cell adhesion by interfering with adhesion receptors in the cell and further release of growth factors that lead to a vicious membrane [47, 57]. Tumour-host interactions are mediated cycle of bone destruction and growth of local tumour [13, by a number of cell surface adhesion molecules which 71, 72]. belong to the four superfamilies of integrins, cadherins, immunoglobulins, and selectins. The acquisition of invasive 9. Osteolytic Metastasis Pathogenesis and diffusive properties by cancer cells are clearly connected with changes in these molecules, especially a fall in the Tumour cells produce IL-1-6-8-11, PgE2, TGFα,TGFβ, expression of E-cadherin and a rise in that of CD44 [58]. EGF, VEGF, TNF, CSF-1, GM-CSF, and M-CSF, which can The expression of adhesion molecules such as integrins directly or indirectly stimulate osteoclastic activity and then αIIbβ3and αLβ2, or PECAM-1, ICAM-1 and N-CAM, plays bone resorption [5, 12, 13, 72, 73]. Proteolytic enzymes, a relevant role in the interaction of cancer cells with the as acid phosphatase, acid hydrolase, alkaline phosphatise endothelium and matrix [59–61]. Preferential localization in [74], metalloproteinase MMP-2, MMP-9, and K cathepsin skeletal segments which contain red bone marrow (vertebral seemed to be involved in the early phase of bone metastasis bodies, ribs, iliac bones, the sternum, the femoral head, the formation degrading bone basal membrane, facilitating epiphysis of long bones) can be explained by the fact that tumoral diffusion and bone matrix cytokine release and the rich vascularity allows cancer cells to be transported to stimulating tumour cell proliferation [75]. Tumour cells may this level and reduced blood flow velocity [62], together with increase bone resorption also stimulating the tumour-linked the formation of vortices and/or microthrombi, promotes immune response with release of osteoclastic activating factors [76]. PTHrP produced by breast cancer cells plays a the adhesion and immobilization of the tumour cells on the endothelial ones. Another theory suggests that neoplastic key role in bone resorption stimulating osteoclastic activity cells migrate to and localize in a preferential target tissue [77, 78]; it is more present in metastatic breast cancer because that is where they find the most fertile “soil” in which (92%) than in not metastatic ones (50% ) [79]. PTHrP and to grow, because the bone and bone marrow cells contain IL 1-6-11 induce osteoclastic bone resorption stimulating and express a variety of growth factors, cytokines, enzymes, osteoblasts and stromal cells to produce the receptor acti- and hormone-like substances which, together with similar vator of nuclear factor-kB (RANK) ligand; this factor links factors produced by cancer cells, can make the bone microen- to its receptor on the osteoclastic precursors inducing their vironment (the “soil”) suitable for cellular implantation (the proliferation and differentiation (Figure 2)[76]. The bone “seeding”) and development [39, 63–66]. MMPs, BSP, and damage consequently obtained facilitates the growth factors OPN play a key role in the implantation of neoplastic cells in release causing tumour cells proliferation, as TGFβ, IGFs, bone marrow by degrading the extracellular matrix modify- FGFs, PDGF, BMPs, which stimulates PTHrP production ing cell-cell and cell-matrix contacts and interactions regula- and then osteolysis [12, 80]. So a vicious circle is present tion of attachment and chemotactic migration of endothelial (Figure 3): osteolysis and growth factors release stimulate cells, and the promotion of angiogenesis [40, 49, 57, 67, 68]. tumour cells proliferation and then metastatic cells growth After their localization in bone marrow spaces, their growth [72, 80]. Usually OPG production by osteoblasts neutralizes International Journal of Surgical Oncology 5 Cancer cells Osteoprotegerin Osteoclast 1,25-dihydroxyvitamin D3 NF-κBand RANKL PTH JNK pathways Interleukin-6, PGE2, tumor necrosis factor, M-CSF RANK Stromal cell Osteoclast Interleukin-11 precursor Bone Postaglandin E2 Parathyroid Osteoclast hormone-related peptide Figure 2: Receptor Activator of Nuclear Factor k B Ligand (RANK) and Osteoclast Formation, from Roodman G. D., “Mechanisms of Bone bone metastasis,” NEnglJMed., 15; 350 (16): 1655–64, Apr 2004. RANK ligand locking osteclastic stimulation, but it has been demonstrated that OPG release is reduced in MCF-7 TGF-β, IGFs, FGFs, PDGF, BMPs estrogen-dependent breast cancer cell line stimulating also osteoclastic activity [81]. Also IL-6 expressed in prostate and Figure 3: The Vicious Circle of Osteolytic Metastasis, from Rood- breast cancer cells stimulates osteoclasts cells strengthening man G. D., “Mechanisms of bone metastasis,” NEnglJMed., 15; 350 the effects of PTHrP onto osteoclasts [82, 83]. (16): 1655–64, Apr 2004. 10. Osteoblastic Metastasis Pathogenesis lesions. After the tumour progression, the balance between Bone blastic metastasis is usually present in prostate cancer. Wnt and its inhibitors is shifted towards the first, promoting Growth factors as TFGβ, PDGF, BMPs, IGFs, FGFs, and l’u- osteoblastic lesions [95, 96]. Nevertheless, PSA tumour- PA (which stimulates TGFβ release) have been isolated in induced can block PTHrP [97] and then bone resorption prostate cancer cells and stimulate osteoblastic differentia- and activating osteoblastic growth factors as TGFβ,l’IGF-1 tion and they have a role in growing and survival tumour released by bone during metastastic development, leading to cells itself [70, 74, 84, 85]. It has been demonstrated that a vicious circle also for osteoblastic lesions [13]. endothelin 1 level is elevated in bone metastatic prostate tumours than in nonmetastatic ones [86]. It stimulates os- Abbreviations teoblastic activity and inhibits the osteoclastic one [87], increases cancer cells proliferation, and stimulates the other ACS: American Cancer Society growth factors mitogen effects [88]; its production is reduced PTHrP: Parathyroid-related peptide by androgens and is increased in the androgen-resistant uPA: Urokinase-tipe plasminogen activator diseases [89]; it is important because usually prostate cancer MMPs: Matrix metalloproteinases develops androgene resistance. ET-1 antagonists reduce BSP: Bone sialoprotein either osteoblastic bone metastatic growth or tumour growth OPN: Osteopontin [90]. Also PTHrP and its receptor have been found in bone IL: Interleukins metastases and in primary prostate cancer, and it has been PGE2: Prostaglandin E2 demonstrated that prostate tumour cells are able to directly TGF: Transforming growth factor express a form of RANK ligand, which directly induces bone EGF: Epidermal growth factor resorption [91], revealing that osteolytic activity is present in VEGF: Vascular endothelial growth factor prostate cancer [92]. Bone degradation products have been TNF: Tumor necrosis factor found in urine leading to the hypothesis that in prostate CSF: Colony stimulating factor cancer there is at the beginning an osteolytic activity followed GM-CSF: Granulocyte macrophage-colony stimulating by high osteoblastic one [93]. Another study demonstrated factor that the insertion of PC-3 tumour cells in SCID mice tibia M-CSF: Monocyte-colony stimulating factor caused osteolytic lesions due to RANK ligand, while other RANK: receptor activator of nuclear factor cell lines caused osteoblastic ones, so authors reported that IGF: Insulin-like growth factor osteoclastic activity is not a prerequisite for osteoblastic FGF: Fibroblast growth factor lesions [94]. Further study is necessary for this [13]. More- PDGF: Platelet-derived growth factor over, in prostate cancer Wnt induces osteoblastic activity, BMP: Bone morphogenetic protein that in the early phase may be balanced by DKK1 Wnt agonist OPG: Osteoprotegerin (an osteoblastic differentiate inhibitor), leading to lythic ET: Endothelin. 6 International Journal of Surgical Oncology References [21] P. R. Algra, J. J. Heimans, J. Valk, J. J. Nauta, M. Lachniet, and B. 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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 107969, 8 pages doi:10.1155/2011/107969 Review Article 1 1 2 1 Giulio Maccauro, Maria Silvia Spinelli, Sigismondo Mauro, Carlo Perisano, 1 2 Calogero Graci, and Michele Attilio Rosa Department of Orthopaedics and Traumatology, Agostino Gemelli Hospital, Catholic University, L.go F. Vito, 1-00168 Rome, Italy Department of Orthopaedics, Messina University, Via Consolare Valeria, 1-98122 Messina, Italy Correspondence should be addressed to Giulio Maccauro, giuliomac@tiscali.it Received 7 February 2011; Accepted 1 June 2011 Academic Editor: Alessandro Gasbarrini Copyright © 2011 Giulio Maccauro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The metastasis is the spread of cancer from one part of the body to another. Two-thirds of patients with cancer will develop bone metastasis. Breast, prostate and lung cancer are responsible for more than 80% of cases of metastatic bone disease. The spine is the most common site of bone metastasis. A spinal metastasis may cause pain, instability and neurological injuries. The diffusion through Batson venous system is the principal process of spinal metastasis, but the dissemination is possible also through arterial and lymphatic system or by contiguity. Once cancer cells have invaded the bone, they produce growth factors that stimulate osteoblastic or osteolytic activity resulting in bone remodeling with release of other growth factors that lead to a vicious cycle of bone destruction and growth of local tumour. 1. Introduction who will die of cancer in 2010, almost all will have metastasis to some part of the body. It is estimated that about 350,000 The metastasis is the spread of cancer from one part, where people die with bone metastasis each year in the United States it started (called its primary site) of the body to another. [5]. Sometimes bone metastasis is not clinically visible and A tumour formed by cells that have spread is called a their demonstration occurs during autopsy; therefore, the “metastatic tumour” or a “metastasis.” The metastatic tum- real incidence of bone metastasis is not possible to report our contains cells that are like those in the original (primary) [6]. Bone metastasis is actually much more common than tumour [1]. When cells break away from a cancerous tumour, primary bone cancers [2, 7] because the incidence is 25/1 they can travel to other areas of the body through the and they are the neoplastic lesions more seen by orthopedist bloodstream or lymph system. From there, they can end up [8, 9]. Bones are the most common place for metastasis in any organ or tissue. Many of the cancer cells that break off after lung and liver [2, 3, 10]. Primary tumors that most from the original tumour die without causing any problems. often leads to bone metastasis are in the order of incidence: Some, however, settle in a new area. There, they begin to prostate, breast, kidney, lung, and thyroid cancer [6]. The grow and form new tumours. Sometimes metastatic tumours incidence of skeletal metastasis from autopsy studies is of are found by tests that are done when the primary cancer is 73% (range of 47–85%) in the breast cancer, 68% (range first diagnosed. In other cases, the metastasis is found first, of 33–85%) in the prostate cancer, 42% (range of 28–60%) causing the doctor to look for the place that the cancer started in the thyroid cancer, 36% (range of 30–55%) in the lung [2, 3]. cancer, 35% (range of 33–40%) in the kidney cancer, 6% (range of of 5–7%) in the esophageal cancer, 5% (range of 3–11%) in the gastrointestinal tract cancers, 11% (range of 2. Epidemiology 8–13%) in the rectal cancer [11]. Given the high prevalence Approximately two-thirds of patients with cancer will of breast, prostate, and lung cancer, they are responsible for develop bone metastasis [4]. Of the estimated 569,490 people more than 80% of cases of metastatic bone disease [12]. 2 International Journal of Surgical Oncology According to Roodman GD, up to 70% of patients with your usual activities and lifestyle [2]. A spinal metastasis may breast cancer or prostate cancer, and 15 to 30% of patients cause pain, instability, neurological injuries with loss of con- with lung, colon, bladder, or kidney cancer develop bone trol urinary and rectal sphincter up to paraplegia. However, metastasis [13]. Breast cancer is the most common malignant 60% of all bone metastasis [26] and 36% of vertebral lesions tumour and the main cause of bone metastasis in women [27] are asymptomatic and discovered occasionally. Symp- [14]. About 70% of people who die from breast cancer will tomatic spinal cord involvement occurs in 18 000 patients per have radiological evidence of skeletal metastasis before their year [18]. Brihaye et al. analyzed 1477 cases concluded that death and in 40% of cases the bone is the first metastatic 16.5% of spinal metastases with epidural involvement came site [11]; the estrogen receptors [11], the sialoprotein [15], from the breast cancer, 15.6% from the lung cancer, 9.2% the parathyroid-related peptide (PTHrP) [16], and 69 gene from prostate cancer, and 6.5% from kidney cancer; they also signature correlated with fibroblasts growth factors [17]are analyzed 1585 cases of symptomatic epidural metastases and predictive markers of bone recurrence [12]. While prostate reported that 70.3% had involvement of thoracic and thora- and lung metastasis are those that occur more in men [14]. columbar region, 21.6% of the lumbar and sacral region, and The primary tumor cannot be determined in 9% of cases of 8.1% of the cervical and cervical-thoraco region, concluding spinal metastases [18]. that although the lumbar region is more involved, the ma- jority of patients with neurological dysfunction have thoracic lesions [28]. 3. Locations of Spine Metastasis Metastasis can occur in any bone in the body but is most 5. Prognosis often found in bones near the center of the body. The spine is the most common site of bone metastasis [2, 12]. It is esti- Once cancer has spread to the bones or to other sites in mated that over the 10% of patients with cancer will develop the body, it is rarely able to be cured, but often it can still a symptomatic spinal metastasis [19, 20]. Algra et al. suggest be treated to shrink, stop, or slow its growth. Even if cure that the initial anatomic location of metastases within is no longer possible, treating the cancer may be able to vertebrae is in the posterior portion of the body. Analysis of help you live longer and feel better [2]. The diagnosis of CT scans shows that the body is involved before the pedicles, metastasis changes the patients’ prognosis; according to data although destruction of the pedicles is the most common from the ACS, the survival rate at five years in nonmetastatic finding on plain films. Destruction of the pedicles occurs carcinomas treated from 1996 to 2002 was of 100% in only in combination with the involvement of the vertebral prostate cancer, 97% in the thyroid cancer, 89% in the breast body [21]. Other common sites are the hip bone (pelvis), cancer, 66% in the kidney cancer, and 16% in the lung cancer; upper leg bone (femur), upper arm bone (humerus), ribs, in the same period, in the metastatic tumors at presentation, and the skull [2, 14]. Studies showed that the thoracic spine the five-year survival rate was of 56% in thyroid cancer, 33% is the region more involved with metastasis [22], while others in prostate cancer, 26% in breast cancer, 10% in renal cancer, studies highlighted how the lumbar spine is more involved and 2% in lung cancer [29]. [23, 24]. The cervical spine is the least involved (10%) [14]. More than 50% of patients with spinal metastasis have 6. Method of Dissemination multiple levels involved, and 10 to 38% of patients have multiple, noncontiguous segments involved [14]. The lung The cancer can metastasize in the bone through different and breast cancers metastasize preferably in the thoracic ways of propagation: the most frequent is the hematogenous region because the venous drainage of the breast through way, the intravenous one for lesions of the spinal column, the azygos communicates with the plexus of Batson in the and the arterial one for lesions that at the beginning are prox- thoracic region [21, 23, 25], while lung cancer drains through imal (shoulder and pelvis) and then distal (elbow and knee). the pulmonary veins in the left heart and from there is Less frequent lesions are those ones by contiguity and even distributed in the generalized manner in the skeletal; prostate less frequent are those ones for lymphatic spread (whose role cancer metastasizes usually to the lumbar-sacral spine and is not well defined) [6, 14]. The diffusion through the venous pelvis, because it drains through the pelvic plexus in the lum- system is the principal process of spinal metastasis. In 1940, bar region [25]. Colon and rectal tumors usually metastasize Batson (Figure 1) demonstrated by injecting contrast into through the portal system in the liver and lung, and only late the vein of the penis in males and into the veins of the breast in skeletal [14]. in women that the contrast and so the tumor cells spread in the blood into the spinal veins as a result of venous reflux that occurred after an increase of intrathoracic pressure and/or 4. Symptoms of Bones and Spine Metastasis intra-abdominal as for a Valsalva maneuver [30]. It was an Bone metastasis is one of the most frequent causes of pain in explanation of the possibility of the diffusion of breast cancer people with cancer. When a cancer spreads to the bone, it can in the column that is drained mainly by the azygos vein make the bones weaker and even cause them to break without which communicates with the paravertebral venous plexus an injury [2, 7]. As the cancer cells damage the bones, of Batson in the thoracic region and prostate cancer that is calcium is released into the blood. This can lead to problems drained from the venous plexus which communicates with from high blood calcium levels. Bone metastasis can also the pelvic plexus of Batson at the lumbar [31]. This hypoth- cause other problems that can limit your ability to keep up esis was confirmed by the study of Coman and DeLong, who International Journal of Surgical Oncology 3 (a) (b) Figure 1: Batson venous plexus, from Batson O.V., “The function of the vertebral veins and their role in the spread of metastases,” Ann Surg. 1940 July; 112 (1): 138–149. noted that lumbar spinal tumor metastasis appeared in 70% normal conditions deviate 5–10% of blood in the vertebral of the animals, injecting cancer cells into the femoral vein venous system and with the latter [14, 23, 30, 33, 34]. Cancer of rats, when an external abdominal pressure was carried cells may metastasize through the blood system and into the out [23, 32]. The venous plexus of Batson is a system of vertebral body directly through the nutrient arteries as in the veins located in the epidural space between the spinal column case of lung cancer [14, 35]. Arguello et al. showed that the bone and the dura mater, with no valves that control the injection of a variety of tumor cells into the systems arterial flow of blood, so that each increase of pressure in the system circulation of mice resulted in a syndrome of tumor coloniza- of the vena cava results in an increased flow level of the tion of the vertebra followed by a spinal cord compression plexus. It is connected to the portal and caval system that in [36]. The direct diffusion of prostate cancer at the lumbar 4 International Journal of Surgical Oncology spine and the direct diffusion of the breast and lung ones at to clinically manifest metastases depends on a number of the thoracic spine are other methods of spreading [14]. promoting or inhibiting conditions, primarily on interaction with surrounding bone and bone marrow cells, through the increased expression of adhesion molecules, the availability 7. Mechanism of Localization of of space, degree of vascularity, and type of bone remodelling. Metastases in Bone The development of a metastasis obviously depends on The development of a bone metastasis is not a simple process the proliferation of neoplastic cells, but other processes are of transport, arrest, and growth of cancer cells in these critical in this connection, primarily neo-angiogenesis [69]. spaces. Before moving to the bone marrow and taking root and growing in its spaces, neoplastic cells have to follow a 8. Pathogenesis long route [37]. They must first spread through the primary site at the expense of the preexisting cells and stroma then The bone tissue undergoes a continuous process of resorp- detach from it by the reduction of adhesion molecules and tion by the action of osteoclasts, and remodelling, through the opening of the epithelial basal lamina, afterwards reach the action of osteoblasts. In normal individuals, this process the blood vessels and penetrate into them by degradation is balanced. In cancer cells, this balance is lost and lytic, thick- of their basal lamina and endothelium, then migrate with ener, or mixed lesions are created [12, 13]. The osteolytic lesions are caused by stimulation of osteoclastic activity the bloodstream and escape the surveillance of the immune cells, reach the bone marrow sinusoids, stop and grow there accompanied by reduced osteoblastic activity not by direct [38, 39]. These processes mainly occur through the activity effects of tumour cells on the bone [70, 71]. The osteoblastic of proteinases, such as the metalloproteinases, the serine, lesions are expression of an increased bone formation around cysteine, and aspartic proteinases [40–53], stromelysin [54], the tumour cells associated with a disequilibrium of the uPA [55, 56]. These proteinases destroy the epithelial basal osteolytic activity and with an altered turnover of the bone lamina and the surrounding tissue by degradation of type [71]. Once cancer cells have invaded the bone, they produce IV collagen, laminin, proteoglycans, and other proteins but growth factors that directly stimulate osteoclastic activity and/or osteoblastic activity resulting in bone remodelling also uncover hidden biologic activities and reduce cell-to-cell adhesion by interfering with adhesion receptors in the cell and further release of growth factors that lead to a vicious membrane [47, 57]. Tumour-host interactions are mediated cycle of bone destruction and growth of local tumour [13, by a number of cell surface adhesion molecules which 71, 72]. belong to the four superfamilies of integrins, cadherins, immunoglobulins, and selectins. The acquisition of invasive 9. Osteolytic Metastasis Pathogenesis and diffusive properties by cancer cells are clearly connected with changes in these molecules, especially a fall in the Tumour cells produce IL-1-6-8-11, PgE2, TGFα,TGFβ, expression of E-cadherin and a rise in that of CD44 [58]. EGF, VEGF, TNF, CSF-1, GM-CSF, and M-CSF, which can The expression of adhesion molecules such as integrins directly or indirectly stimulate osteoclastic activity and then αIIbβ3and αLβ2, or PECAM-1, ICAM-1 and N-CAM, plays bone resorption [5, 12, 13, 72, 73]. Proteolytic enzymes, a relevant role in the interaction of cancer cells with the as acid phosphatase, acid hydrolase, alkaline phosphatise endothelium and matrix [59–61]. Preferential localization in [74], metalloproteinase MMP-2, MMP-9, and K cathepsin skeletal segments which contain red bone marrow (vertebral seemed to be involved in the early phase of bone metastasis bodies, ribs, iliac bones, the sternum, the femoral head, the formation degrading bone basal membrane, facilitating epiphysis of long bones) can be explained by the fact that tumoral diffusion and bone matrix cytokine release and the rich vascularity allows cancer cells to be transported to stimulating tumour cell proliferation [75]. Tumour cells may this level and reduced blood flow velocity [62], together with increase bone resorption also stimulating the tumour-linked the formation of vortices and/or microthrombi, promotes immune response with release of osteoclastic activating factors [76]. PTHrP produced by breast cancer cells plays a the adhesion and immobilization of the tumour cells on the endothelial ones. Another theory suggests that neoplastic key role in bone resorption stimulating osteoclastic activity cells migrate to and localize in a preferential target tissue [77, 78]; it is more present in metastatic breast cancer because that is where they find the most fertile “soil” in which (92%) than in not metastatic ones (50% ) [79]. PTHrP and to grow, because the bone and bone marrow cells contain IL 1-6-11 induce osteoclastic bone resorption stimulating and express a variety of growth factors, cytokines, enzymes, osteoblasts and stromal cells to produce the receptor acti- and hormone-like substances which, together with similar vator of nuclear factor-kB (RANK) ligand; this factor links factors produced by cancer cells, can make the bone microen- to its receptor on the osteoclastic precursors inducing their vironment (the “soil”) suitable for cellular implantation (the proliferation and differentiation (Figure 2)[76]. The bone “seeding”) and development [39, 63–66]. MMPs, BSP, and damage consequently obtained facilitates the growth factors OPN play a key role in the implantation of neoplastic cells in release causing tumour cells proliferation, as TGFβ, IGFs, bone marrow by degrading the extracellular matrix modify- FGFs, PDGF, BMPs, which stimulates PTHrP production ing cell-cell and cell-matrix contacts and interactions regula- and then osteolysis [12, 80]. So a vicious circle is present tion of attachment and chemotactic migration of endothelial (Figure 3): osteolysis and growth factors release stimulate cells, and the promotion of angiogenesis [40, 49, 57, 67, 68]. tumour cells proliferation and then metastatic cells growth After their localization in bone marrow spaces, their growth [72, 80]. Usually OPG production by osteoblasts neutralizes International Journal of Surgical Oncology 5 Cancer cells Osteoprotegerin Osteoclast 1,25-dihydroxyvitamin D3 NF-κBand RANKL PTH JNK pathways Interleukin-6, PGE2, tumor necrosis factor, M-CSF RANK Stromal cell Osteoclast Interleukin-11 precursor Bone Postaglandin E2 Parathyroid Osteoclast hormone-related peptide Figure 2: Receptor Activator of Nuclear Factor k B Ligand (RANK) and Osteoclast Formation, from Roodman G. D., “Mechanisms of Bone bone metastasis,” NEnglJMed., 15; 350 (16): 1655–64, Apr 2004. RANK ligand locking osteclastic stimulation, but it has been demonstrated that OPG release is reduced in MCF-7 TGF-β, IGFs, FGFs, PDGF, BMPs estrogen-dependent breast cancer cell line stimulating also osteoclastic activity [81]. Also IL-6 expressed in prostate and Figure 3: The Vicious Circle of Osteolytic Metastasis, from Rood- breast cancer cells stimulates osteoclasts cells strengthening man G. D., “Mechanisms of bone metastasis,” NEnglJMed., 15; 350 the effects of PTHrP onto osteoclasts [82, 83]. (16): 1655–64, Apr 2004. 10. Osteoblastic Metastasis Pathogenesis lesions. After the tumour progression, the balance between Bone blastic metastasis is usually present in prostate cancer. Wnt and its inhibitors is shifted towards the first, promoting Growth factors as TFGβ, PDGF, BMPs, IGFs, FGFs, and l’u- osteoblastic lesions [95, 96]. Nevertheless, PSA tumour- PA (which stimulates TGFβ release) have been isolated in induced can block PTHrP [97] and then bone resorption prostate cancer cells and stimulate osteoblastic differentia- and activating osteoblastic growth factors as TGFβ,l’IGF-1 tion and they have a role in growing and survival tumour released by bone during metastastic development, leading to cells itself [70, 74, 84, 85]. It has been demonstrated that a vicious circle also for osteoblastic lesions [13]. endothelin 1 level is elevated in bone metastatic prostate tumours than in nonmetastatic ones [86]. It stimulates os- Abbreviations teoblastic activity and inhibits the osteoclastic one [87], increases cancer cells proliferation, and stimulates the other ACS: American Cancer Society growth factors mitogen effects [88]; its production is reduced PTHrP: Parathyroid-related peptide by androgens and is increased in the androgen-resistant uPA: Urokinase-tipe plasminogen activator diseases [89]; it is important because usually prostate cancer MMPs: Matrix metalloproteinases develops androgene resistance. ET-1 antagonists reduce BSP: Bone sialoprotein either osteoblastic bone metastatic growth or tumour growth OPN: Osteopontin [90]. Also PTHrP and its receptor have been found in bone IL: Interleukins metastases and in primary prostate cancer, and it has been PGE2: Prostaglandin E2 demonstrated that prostate tumour cells are able to directly TGF: Transforming growth factor express a form of RANK ligand, which directly induces bone EGF: Epidermal growth factor resorption [91], revealing that osteolytic activity is present in VEGF: Vascular endothelial growth factor prostate cancer [92]. Bone degradation products have been TNF: Tumor necrosis factor found in urine leading to the hypothesis that in prostate CSF: Colony stimulating factor cancer there is at the beginning an osteolytic activity followed GM-CSF: Granulocyte macrophage-colony stimulating by high osteoblastic one [93]. Another study demonstrated factor that the insertion of PC-3 tumour cells in SCID mice tibia M-CSF: Monocyte-colony stimulating factor caused osteolytic lesions due to RANK ligand, while other RANK: receptor activator of nuclear factor cell lines caused osteoblastic ones, so authors reported that IGF: Insulin-like growth factor osteoclastic activity is not a prerequisite for osteoblastic FGF: Fibroblast growth factor lesions [94]. Further study is necessary for this [13]. More- PDGF: Platelet-derived growth factor over, in prostate cancer Wnt induces osteoblastic activity, BMP: Bone morphogenetic protein that in the early phase may be balanced by DKK1 Wnt agonist OPG: Osteoprotegerin (an osteoblastic differentiate inhibitor), leading to lythic ET: Endothelin. 6 International Journal of Surgical Oncology References [21] P. R. Algra, J. J. Heimans, J. Valk, J. J. Nauta, M. Lachniet, and B. 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