An overview of current and future treatment
options for chondrosarcoma
Chen-Ming Su1, Yi-Chin Fong2,3 , and Chih-Hsin Tang1,4,5*
1Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
2School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan 3Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
4Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan 5Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
*Corresponding author
Chih-Hsin, Tang PhD
Graduate Institute of Basic Medical Science, China Medical University No. 91, Hsueh-Shih Road, Taichung, Taiwan
Tel: (886) 4-22052121 Ext. 7726. Fax: (886) 4-22333641. E-mail: chtang@mail.cmu.edu.tw 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Abstract
Introduction: Chondrosarcoma is the most common primary bone tumor. It is
difficult to diagnose, as it is a rare, greatly diverse, complex, and distinct disease, and it responds poorly to both chemotherapy and radiation treatment. For now, the ideal treatment for low-grade chondrosarcoma can be intralesional curettage and additional radiotherapy or chemotherapy would be severe overtreatment. However, many recent studies have focused on the development of new anticancer strategies or chemotherapeutic agents derived from naturally comestible resources such as terrestrial herbs, new compounds, and molecular targeting proteins for the treatment
of chondrosarcoma.
Areas covered: In this review, we give an overview of current treatment options,
including new compounds targeting to hedgehog, Bcl-2 inhibtion, targeting to mammalian target of rapamycin (mTOR) and Src inhibtion; alternative medicines like benzimidazole, phloroglucinol and trichodermin derivatives; herbal medicines such as epigallocatechin-3-gallate, berberine and curcumin; cytogenetic approaches, including isocitrate dehydrogenase 1/2 and lysine-specific demethylase 1; and related therapeutic target proteins, which have the potential to improve treatment of patients with chondrosarcoma.
Expert opinion: The most promising approach for the treatment of human
chondrosarcoma that is currently available includes a combination of experimental therapeutic options and sufficient surgical resection. Fortunately, many recent studies regarding tumor angiogenesis are providing new important information about chondrosarcoma therapies, and for this reason, we believe that a novel and effective therapy will be developed in the near future.
Key words: chondrosarcoma, chemotherapy, treatment, cytogenetics, apoptosis
1. Introduction
1.1.
Chondrosarcoma
Bone tumors cause high mortality, and chondrosarcomas account for approximately 30% of all skeletal system tumors. Chondrosarcomas are composed of a heterogeneous group of malignant tumors that appear in the cartilage matrix. The overall prevalence of chondrosarcomas is 1 per 20,000 populations [1]. It accounts for up to 27% of all primary malignant sarcomas, and it is a well-studied neoplasm compared with the more aggressive osteosarcoma [2, 3]. Most chondrosarcomas are of the conventional hyaline cartilage type that mainly arise in adulthood and old age, 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
peaking in the fourth to sixth decades of life and affecting males more than females [4].
Most chondrosarcomas occur in the thoracic, pelvic, and long bones. However, the accurate origin of chondrosarcoma is still indistinct because it is difficult to demonstrate whether an individual chondrosarcoma is derived from an enchondroma or osteochondroma precursor. In recent studies, some benign tumors require an accurate diagnosis by the clinical and imaging features, including chondromas of the hands and feet [5], periosteal chondromas [6], synovial chondromatosis [7], and enchondromatosis of Maffucci syndrome and Ollier disease [8]. In contrast to accurate diagnosis of benign tumors, malignant transformation is associated with gene mutations such as parathyroid hormone 1 receptor or exostosin-1 (EXT-1) and
EXT-2 mutations in response to Bcl-2 and hedgehog signaling, respectively,
although the incidence of malignant transformation derived from benignancy may be extremely rare [9, 10].
There are several ways to classify chondrosarcomas based on clinical, histological, or pathological traits, and as such, soft tissue tumors can be categorized into benign; intermediate – locally aggressive; intermediate – rarely metastasizing; and malignant in response to their biological potential (World Health Organization [WHO] classification [11]). Those tumors that arise de novo in extraskeletal tissue or in other tumors are called primary chondrosarcomas, whereas those that arise in previously benign cartilaginous tumors such as enchondroma or osteochondroma are secondary chondrosarcomas [12]. In addition, chondrosarcoma is divided into central, peripheral or periosteal/juxtacortical classifications, based on the location of the cartilaginous lesion. Central chondrosarcoma, which is atypical cartilaginous tumor/grade 1 chondrosarcoma, often arises in the appendicular skeleton [11], and peripheral chondrosarcoma arises either on an osteochondroma or directly from the surface of a bone, whereas periosteal/juxtacortical chondrosarcoma may arise as an exostosis of the cartilaginous cap [13]. The classification of chondrosarcomas can be further stratified into numerous histological subtypes, including conventional (account for approximately 80% of cases), dedifferentiated, clear cell and
mesenchymal chondrosarcomas [14].
1.2.
Conventional chondrosarcomas
Conventional chondrosarcomas are subdivided into three grades as follows: grade 1 (low grade), which is the most common and can be difficult to differentiate from enchondroma; grade 2 (intermediate); and grade 3 (high grade) according to the degree of cellularity and nuclear atypia. Consequently, conventional chondrosarcomas make up approximately 90% of low-to-intermediate grade tumors that are characterized by indolent clinical behavior and low metastatic potential [15]. However, the incidence of conventional chondrosarcoma is rare, representing only 15% of all malignant bone tumors. Conventional chondrosarcomas present with a median age of 45 years, but in < 10% of cases, it occurs in children, with expeditious 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103
mortality [16, 17].Patients with Ollier disease and Maffucci syndrome have a higher incidence of chondrosarcomas, and while it generally presents at a younger age in these patients than in the general population, it does not seem to be transmitted in a Mendelian manner [18]. High-grade chondrosarcoma might exhibit necrosis, cysts and hemorrhage. The clinical prognosis of conventional chondrosarcoma is related to grade; 5-year survival rate ranges from 90% for grade 1 to 40% for grade 3. Local recurrence without metastasis significantly increases mortality requiring long-term
follow-up care [19].
1.3.
Dedifferentiated chondrosarcomas
Dedifferentiated chondrosarcoma is defined by the development of a malignant biphasic tumor with a high-grade, non-cartilaginous component, and it is typically classified as low- to intermediate-grade conventional chondrosarcoma [20]. Thus, the incidence of this tumor is approximately 11% of all chondrosarcomas. It typically presents in the fifth to sixth decades of life with both sexes affected equally. In clinical practice, the 5-year survival rate with this tumor is < 24% in case
with pathological fractures, pelvic localization, increasing age or metastasis [21].
1.4.
Clear cell chondrosarcomas
The first tumors were defined as clear cell chondrosarcoma in 1976 [22]. The clear cell type is unusually epiphyseal in location in contrast with other metaphyseal chondrosarcoma. Clear cell chondrosarcoma is the rarest subtype of chondrosarcoma, making up 1- 2% of all cartilaginous tumors. It often presents at a younger age than conventional chondrosarcoma and has a 2:1 male-to-female ratio [23]. Because this tumor can be osteolytic or sclerotic and sometimes present with marginated calcification, it often has a benign radiological appearance or is given a mistaken diagnosis of chondroblastoma, which is a benign chondroid-producing tumor. In clinical practice, the insufficient eradication of intralesional curettage may lead to a 15% recurrence rate, resulting in metastasis and mortality [24].
1.5.
Mesenchymal chondrosarcomas
Mesenchymal chondrosarcoma is a rare variant of chondrosarcoma; just like the clear cell type, it occurs in the second to third decade of life at an equal frequency in males and females, similar to dedifferentiated chondrosarcoma. This tumor was initially described in 1959 as a high-grade malignant biphasic neoplasm of benign cartilage with primitive small round blue cells [25, 26]. After an initial clinical diagnosis of mesenchymal chondrosarcoma, a 5-year survival rate of 52% is observed, and recurrence and pulmonary metastasis may occur over a long interval [27, 28].
1.6.
Current treatment
Chondrosarcomas are a greatly diverse and complex group of distinct diseases, and 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145
their treatment typically includes a multidisciplinary approach. In the past several decades, the clinical treatment of chondrosarcoma has remained a challenging problem. Until now, the only curative approach to conventional primary central chondrosarcoma, including clear cell chondrosarcoma and periosteal origin chondrosarcoma (i.e. the vast majority of the forms) is adequate surgical resection, although complete resection of low- to intermediate-grade tumors is often curative [2]. Chemotherapy is not still considered a valuable adjuvant therapy but only possibly effective in the mesenchymal chondrosarcoma, while radiotherapy is not usually applied in any subtype even in advanced tumor with the exception of axial tumors. In clinical settings, patients undergoing either surgical resection or aggressive chemotherapy have major concerns about the potential for local recurrence, the impact of adjuvant treatment on wound healing, and the possible toxic side effects as a result of these treatments. Despite that, surgical resection with wide margins remains the primary remedy against recurrence and metastasis of chondrosarcoma. Furthermore, this disease is often inadequately diagnosed and responds poorly to traditional radiotherapy or chemotherapy, resulting in significant morbidity and a low 5-year survival rate. Because of recurrences of this disease after 5 years or even > 10 years, the 5-year survival rate is not indicative of the cure rate [29]. No specific therapy has been proven to be a standard cure for chondrosarcoma; however, many recent studies have focused on developing novel anticancer treatment strategies or chemotherapeutic agents from naturally comestible resources such as terrestrial herbs [30, 31], new chemical compounds, and new target therapies for the treatment of this disease. In this review, we will give an overview of the current new compounds, herbal medicines, and related therapeutic targets that have the potential to improve the treatment of patients with chondrosarcoma is given.
2.
Novel therapy
2.1.
New compounds
2.1.1. Targeting to hedgehog
During a biological process of chondrocyte proliferation and differentiation, both Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) signaling pathways are necessary characters to balance bone development that upregulate IHH leads to proliferation of growth plate chondrocytes, and PTHrP is the opposite of that and down-regulates IHH, thus completing the negative feedback loop [32]. Recently, increasing evidence has demonstrated that the human IHH signaling pathway is potentially associated with tumor development and progression in mesenchymal chondrosarcomas [33, 34]. Furthermore, there have been some inhibitors of the IHH pathway in early phases of clinical development or animal therapy such as vismodegib, LDE 225, saridegib (IPI-926), PF-04449913 and TAK-441[35, 36], although the side effect of vismodegib which is proceeding in phase II clinical trial is 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
dysgeusia [37]. Accordingly, blocking the IHH pathway was shown to be a promising treatment for several benign cartilaginous neoplasms [38].
2.1.2. Bcl-2 inhibition
Because chondrosarcomas present their resistance to conventional chemo- and radiotherapy, Bcl-2 family members, which are anti-apoptotic proteins, play an important role in chemoresistant chondrosarcoma. In addition, Bcl-2 is demonstrated as the downstream signaling molecule of the PTHrP pathway, which has been mentioned in the context and each other has a positive correlation in chondrosarcoma cells [39]; a combination of the BH-3 mimetic ABT-737, inhibitor of Bcl-2 family members and chemotherapy may be beneficial for patients with
chondrosarcoma [40].
2.1.3. Targeting to mammalian target of rapamycin
During the tumor progression of chondrosarcoma, phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway is a common downstream signaling pathway of receptor tyrosine kinases (RTKs), which transfer signals from extracellular domain into the cytoplasm, thus becoming the primary mediators of the signaling network [41]. A recent study has reported that the treatment of BEZ235, a dual PI3K/mTOR inhibitor, decreased the phosphorylation of AKT at the Ser473 site,
suggesting inhibition of the PI3K/mTOR pathway as a promising therapeutic strategy for the treatment of chondrosarcoma [41].
2.1.4. Src inhibition
RTK results in the activation of both PI3K/AKT/mTOR and Src signaling pathways, which are extensively associated with various tumor cells including chondrosarcoma [42]. In addition, the Src pathway has been also revealed with high expression in chondrosarcoma [43]. Recent studies have been reported that dasatinib, a tyrosine kinase inhibitor of Src signaling, not only led to reduction of cell viability but also overcame chemoresistance in chondrosarcoma [42]. Thus, Src inhibition may be an effectively therapeutic strategy of chondrosarcoma. Accordingly, strategies toward the deregulation of the RTK families or downstream such as PI3K/AKT/mTOR and Src signaling pathways have been recognized as a selective anti-cancer targets therapy.
2.2.
Alternative medicines
2.2.1. Benzimidazole derivatives
Because poor prognosis has posed a continuous and serious threat to patients with chondrosarcomas, developing a promising chemotherapeutic agent in human chondrosarcoma cells is a worthwhile priority. Benzimidazole demonstrates therapeutic potential and interacts with biological macromolecules such as enzymes and receptors, resulting in diverse biological activity and clinical applications [44]. 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229
Benzimidazole derivatives are naturally part of the vitamin B12 molecule and provide useful precursors or subunits for the development molecules of pharmaceutical or biological interest. Recently, a new benzimidazole derivative 1-benzyl-2-phenylbenzimidazole (BPB) has been shown to decrease cellular survival and chondrosarcoma tumor growth both in vitro and in vivo [45]. Apoptosis is an intracellular cell death program that can be characterized both morphologically and biochemically [46]. The induction of apoptosis occurs through two alternative pathways, the extrinsic and intrinsic pathway, and it can be a hallmark of promising treatments on chondrosarcoma cells. Accordingly, BPB triggers both extrinsic death receptor (DR)- and intrinsic mitochondria-dependent pathways in two chondrosarcoma cell lines (SW1353 and JJ012), which are both type II solitary tumors. In addition, another new benzimidazole derivative, 2-(furan-2-yl)-5-(piperidin-1-yl)-1-(3,4,5-trimethoxybenzyl)benzimidazole (FPipTB), has demonstrated pro-apoptotic activity on human chondrosarcoma cell lines but not on primary chondrocytes [47]. A variety of toxic consequences, including misfolding, failure of protein synthesis and hypoxia, can spoil endoplasmic reticulum (ER) functioning and thus result in ER stress-derived cell death. Increasing evidence has supported that ER stress plays a crucial role in the regulation of apoptosis [48, 49]. The apoptotic effects of the benzimidazole derivative 5-methyl-2(pyridine-3-yl)-1-(3,4,5-trimethoxybenzyl)benzimidazole (MPTB) not only reduced survival and tumor growth of human chondrosarcoma cells but also revealed a dramatic 44% reduction of the tumor volume in animal studies [50]. The benzimidazole derivatives FPipTB and MPTB-elicited apoptosis from BPB through extrinsic and intrinsic apoptotic pathways, as well as through mitochondrial dysfunction and stimulation of ER stress.
2.2.2. Phloroglucinol derivatives
Increasing evidence indicates that the induction of apoptosis is a promising potential strategy for cancer treatment. Caspases (cysteine-dependent aspartate-directed proteases) are a family of cysteine proteases that consists of initiator (caspases 8, 9, and 12) and executioner proteins (caspases 3 and 7) for the regulation of pathological cell death [51]. Initiator caspases play an integral roles in cellular apoptosis, reducing effector caspases from inactive pro-forms to their activated cleaved form; effector caspases, in turn ,cleave poly-ADP ribose polymerase (PARP), resulting in its nuclear activation and the initiation of the apoptotic process [52]. Numerous phloroglucinol derivatives are recognized to be antioxidants, cancer preventive agents, or even antineoplastic agents. Recently, they have been shown to display noteworthy anticancer activity, resulting in the induction of apoptosis in tumor cells [53, 54]. A new phloroglucinol derivative, 2,4-bis(2-fluorophenylacetyl)phloroglucinol (BFPP), induces apoptotic cell death through the stimulation of ER stress, as indicated by calcium release and the activation of the caspase 12 cascade in human chondrosarcoma cells [55]. Phloroglucinol derivatives 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271
demonstrated novel antitumor activity against human chondrosarcoma cells and in murine tumor models.
2.2.3. Trichodermin derivatives
During the apoptotic process, disruption of oxidative phosphorylation results in the reduction of ATP and loss of mitochondrial transmembrane potential which is derived from oxidative phosphorylation occurring across the inner mitochondrial membrane [56]. While this process generates ATP, it also leads to the appearance of superoxide anion radicals (O2-), which form a sequence of reactive oxygen species
(ROS), including hydrogen peroxide (H2O2) and highly reactive hydroxyl radicals.
This cytotoxic ROS signature appears to trigger apoptosis through pro-apoptotic proteins, thereby altering the mitochondrial-dependent pathway toward tumor progression [57, 58]. Lately, a few studies have demonstrated the antitumor effect of another particularly new compound, a member of the trichodermin species, which is a much more potent inhibitor of protein synthesis and fungal metabolism in mammalian cells [59-61]. Trichodermin was initially isolated from the phytopathogenic fungus Trichoderma spp., which are a medically and pharmacologically important species used for mycotoxin production [62, 63]. Moreover, Su et al. [64] have isolated trichodermin from the fermented broths of
Nalanthamala psidii and revealed their antitumor effect in human chondrosarcoma
cells and their ability to inhibit tumor growth in vivo. Their results indicated that trichodermin induces cellular death both in human chondrosarcoma and osteosarcoma cells but not in primary chondrocytes and osteoblasts, whereas activation of ROS, ER stress and calcium release leads to mitochondrial dysfunction and involves a caspase 12 and caspase 3-mediated apoptotic mechanism in chondrosarcoma. If the role of trichodermin is further confirmed for the treatment of other subgroups, these derivatives will certainly serve as a promising treatment for chondrosarcoma.
2.3.
Herbal medicines
2.3.1. Epigallocatechin-3-gallate
It is well-known that green tea possesses beneficial cancer-preventive activity and inhibitory effects against tumorigenesis and tumor growth [65]. Epigallocatechin-3-gallate (EGCG) is a naturally produced compound and a type of catechin, which is the major component of green tea and has been correlated with a decrease in the risk of developing various cancers [66]. The mechanism of the antitumor effects of EGCG in chondrosarcomas is attributed to the induction of DNA fragmentation through the elevation of caspase 3 activity and cleavage of PARP [67], suggesting that EGCG is a promising potential therapy in human chondrosarcoma cells (HTB-94, grade II chondrosarcoma). EGCG induced apoptosis in chondrosarcoma cells (SW1353 and CRL-7891, grade II chondrosarcoma) via the suppression of tumor cell growth and inhibition of mRNA and protein levels of the transmembrane protein 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313
patched and the transcription factor Gli-1, which are involved in the human IHH signaling pathway [68]. Yang et al. [69] also demonstrated the apoptotic activity of EGCG in human chondrosarcoma cells (JJ012 and sw1353) but not in primary articular chondrocytes, whereas EGCG induced a dose-dependent inhibition of tumor growth in vivo. EGCG increased ROS accumulation by mediating the oxidative stress caused by O2- and H2O2, whereas apoptosis signal-regulating
kinase-1 (ASK-kinase-1) dephosphorylation at Ser967 site and phosphorylation at Thr845 site was
enhanced by EGCG in chondrosarcoma cells. The proposed treatment with EGCG would provide a beneficial approach for the development of potent chemotherapies for the treatment of chondrosarcoma.
2.3.2. Berberine
Berberine is an active component of natural isoquinoline quaternary alkaloids found in several Chinese herbs such as Huanglian [70]. In earlier eras, berberine was used to dye wool, leather, and wood. More recently, it has been shown to have antimicrobial, anti-inflammatory, and antidiabetic effects, and it is able to prevent growth in various cancer cells [71, 72]. Metastasis is one of the most common causes of death in patients with chondrosarcoma. As a matter of fact, berberine has been reported to suppress the metastasis of chondrosarcoma cells by inhibiting integrin performance [73]. Integrins, which form heterodimers of �- and �-subunits, play an important role in tumor-mediated deterioration of the extracellular matrix (ECM), resulting in the invasion and metastasis of chondrosarcomas [74, 75]. Berberine downregulates the expression of �v�3 integrin on the cellular surface through the protein kinase C delta, c-Src and activator protein-1 pathways involving in metastasis of chondrosarcoma. Thus, berberine may become a novel anti-metastasis
therapeutic agent for the treatment of chondrosarcoma.
2.3.3. Curcumin
Curcumin is one of the active chemical ingredients isolated from the spice turmeric, which is derived from the rhizome of the East Indian plant Curcuma longa, and its botanical and nutritional characteristics have been well studied [76]. For several centuries, curcumin has been used as a dietary supplement and has been found to possess antioxidant, antiseptic, analgesic, antimalarial and anti-inflammatory properties [77, 78]. In addition to its involvement in the regulation of mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis in cancer, curcumin-induced antitumor activity has chemotherapeutic potential in various cancers [79, 80]; the most common studies of curcumin are about cancer, ovarian cancer, and pituitary-related conditions [78, 81, 82]. A recent study has described the apoptotic activity of curcumin in human chondrosarcoma cells [83]. During apoptosis, the extrinsic apoptotic pathway begins at membrane DRs such as Fas, DR4 and DR5, and facilitates the binding of the intracellular molecules of proximal caspase 8 and distal executioner caspases [46]. As a result, treatment with 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355
curcumin causes the activation of the extrinsic apoptotic pathway and the induction of cleaved forms of caspases in chondrosarcoma both in vitro and in vivo. This is the first study concerning the treatment of curcumin to induce cell apoptosis in chondrosarcoma.
2.4.
Cytogenetic approaches
2.4.1. p53
Over the past decade, many studies have investigated the targeted therapy of chondrosarcomas through the breaking of molecular genetic structures and deregulation of signaling pathways [84]. Recent studies have proposed that an increased DNA content in tumor cells may indicate a poorer prognosis [85]. Accordingly, several cytogenetic or differential studies in chondrosarcoma have suggested genetic approaches could be a potential therapeutic approach to prevent tumor progression [43, 86, 87]. For instance, studies have revealed that traditional tumor suppressor genes such as p16 and p53 are associated with tumor progression in high-grade chondrosarcomas [88-90]. The characterization of the p53 tumor suppressor gene has played an integral role in tumor progression, and the p53 pathway is involved in 96% of high-grade chondrosarcomas [89]. Consistent with previous studies of the p53 pathway, a few genetic variations, including duplication of 12q13 and deletion of 9p21, result in the alteration of multiple protein-coding genes [91-93]. Nevertheless, the underlying role of somatic and epigenetic alterations in the mechanism of malignant tumor progression in chondrosarcomas is still unclear.
2.4.2. Isocitrate dehydrogenase 1,2
Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have recently been identified
in conventional and periosteal chondrosarcomas [94]. Under normal physiological conditions, IDH1 is located in the cytoplasm and peroxisomes, whereas IDH2 is located in the mitochondria. Due to being the same biochemical reaction, IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate into α-ketoglutarate (α-KG) and CO2, with NADP+ as a cofactor instead of NAD+, which is associated with
Krebs citric acid cycle [95, 96]. However, abnormal IDH1 impaired physiologic function and conferred a gain of function to convert α-KG to D-2-hydroxyglutarate
(D-2-HG), which accumulates to extremely high levels in tumorigenesis suggesting
as a marker of IDH1 mutation [97, 98]. The conserved position of somatic heterozygous IDH1 (R132C and R132H) and IDH2 (R172S) mutations have been observed in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines [99], as well as in 56% of central and periosteal cartilaginous tumors (IDH1>IDH2). Accordingly, some studies have recently shown evidence that AGI-5198 and AGI-6780 potentially inhibited the tumor growth of mutant R132H IDH1 (half-maximal inhibitory concentration (IC50 = 70 nM) and mutant R140Q IDH2
(IC50 ≤ 20 nM), respectively [100, 101], and they should be further investigated in
356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397
the clinic. Thus far, these mutations are related to DNA and histone methylation or variations in the hypoxic response [102] and appear unique to mesenchymal tumors [103], but the exact oncogenic mechanism in tumor progression remains obscure in chondrosarcoma.
2.4.3. Lysine-specific demethylase 1
The epithelial-mesenchymal transition (EMT) is a biological development where epithelial cells undergo biochemical changes to gain a mesenchymal phenotype. This process is also crucial in progressive benign chondrogenic tumor, as it enhances migratory capacity, invasiveness, cell motility, resistance to apoptosis, production of ECM components, and downregulation of E-cadherin with upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin [104, 105]. According to previous studies, many developmentally transcriptional repressor genes in EMT, including Twist, Slug and Snail are involved in bone tumor progression [106, 107]. In 2004, the discovery of the first histone demethylase, lysine-specific
demethylase 1 (LSD1), revealed an important role for histone methyl marks in
pharmacological modulation [108]. Because LSD1-derived epigenetic markers, which are concerned with EMT-driven progression, have been identified in chondrosarcomas and other tumors [109, 110], the potential of tranylcypromine, a non-reversible LSD1 inhibitor, to inhibit tumor growth of LSD1-expressing tumors has provided an additional potential strategy as a combination therapy for
chondrosarcoma.
2.5.
Molecule targeting
2.5.1. Interleukin-6
The combination of conventional chemotherapeutic agents and biological responses to molecular modifiers such as tumor necrosis factor alpha (TNF-α) or interferon gamma (IFN-γ), has been analyzed continuously as an established treatment option for chondrosarcomas [111]. Nevertheless, none of these agents has demonstrated potential activity without severe adverse effects when used as a single agent in this disease [112-114]. As a consequence, efficient new molecular targets are currently being used. Lately, many immunotherapy studies have been shown to be promising treatments for chondrosarcoma [115-117]. Interleukin 6 (IL-6) is secreted by T cells and macrophages to stimulate an immune response in which it is identified as both a pro-inflammatory cytokine and an anti-inflammatory myokine [118, 119]. In addition to its multifunctional role in immunoreaction or biological activities such as energy mobilization, IL-6 has shown to be involved in the development and progression of various tumors, including osteosarcomas, prostate cancers, and chondrosarcomas [117, 120, 121]. Increasing studies have indicated that matrix metalloproteinases (MMPs) 1, 2, 3, 9 and 13 are associated with high histological grade, tumor metastasis, and invasion through autocrine or paracrine pathways [122, 123], as their proteolytic activities assist in the degradation of the ECM and 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439
basement membrane [124, 125]. Tang et al. [126] suggested that IL-6 would help to direct the metastasis of chondrosarcoma cells. IL-6 increased the migration and expression of MMP-13 in human chondrosarcoma cells, and as a result, MMP-13 might be the mediator in response to IL-6, which causes the degradation of the ECM and an increase in tumor migration. In addition, the overexpression of either the IL-6 small hairpin RNA (shRNA) or anti-IL-6 receptor antibody could reduce the migration and MMP-13 expression in chondrosarcoma cells. Therefore, inhibiting the expression of IL-6 by using the strategy of IL-6 shRNA and its receptor antibody
might be a possible treatment of malignant chondrosarcomas.
3. Conclusion
Future studies should capitalize on advances in molecular biology and developmental pharmacology to develop more effective therapies for primary or secondary chondrosarcoma. Herein, we gave an overview of the currently therapeutic options, including new compounds, alternative medicines, herbal medicines, gene therapies and molecular targeting proteins, to the scientific world to be deepened studies to possibly arrive to the bed side of the patients, and further categorized them on the basis of their mechanism of action for the treatment of patients with malignant chondrosarcoma (as shown in Table 1). For those newly synthesized compounds, which acquired derivatives from benzimidozole, phloroglucinol and trichodermin, they have demonstrated the treatment in chondrosarcoma with initial apoptotic pathways through either of that both in vitro and in vivo before clinical investigation. Herbal treatments, including those with EGCG, berberine and curcumin, possessed physiological effects that have demonstrated both non-toxicity in normal cells and antitumor therapies in chondrosarcomas and in various other cancer cells. Of these herbal medicines, those which can induce apoptosis, increase interactions between chondrocytes and the ECM via integrins, and regulate cell migration and invasion are possible therapeutic agents for the treatment of chondrosarcoma. In addition, several oncogenic studies of the specific genetic alterations observed in chondrosarcomas may enable researchers to develop a potential therapeutic approach to halt tumor progression by targeting genes such as p53, IDH1/2, and LSD1, but not all studies are likely to lead to effective targeted therapies. Hence, the high mutation frequency in chondrosarcoma suggests a causal rather than a bystander role for these genetic mutations in tumor development. In addition to those therapeutic options, IL-6 has been suggested as a potential immunotherapeutic target protein in chondrosarcoma cells. However, the treatment of chondrosarcoma involves other targets in several active signaling pathways, including IHH, PTHrP, and Src-Akt, mTOR, as well as Bcl-2 anti-apoptotic protein. Based on the experimental characteristics of the above therapeutic options, some of them should further determine whether they are suitable for the 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481
next clinical trial and the targeted treatment in chondrosarcoma.
4. Expert opinion
The appearance of chondrosarcoma has been discovered over the past several decades, so numerous studies of the therapeutic approaches have been developed in this malignant tumor. Until now, the cause of chondrosarcoma is still not clear just like many other cancers. In addition, biopsy combined with the use of immunohistochemistry is the cornerstone of the chondrosarcoma diagnosis and the determination of the tumor's grade, and if necessary, radiography and other imaging techniques such as computerized tomography, magnetic resonance imaging and bone scan can evaluate the metastasis from chondrosarcoma. In spite of that, we still need a precisely definition that can identify the histologic grading because there is subjective variability of grade 2 chondrosarcoma, which depends on the different experience of interobservers. Hence, there is an imperative need for molecular markers that can be used to make therapeutic principles, predict clinical symptoms, and provide novel therapeutic targets of chondrosarcomas.
Of the studies on genetically modified mice provide a perspective of the therapeutic treatment in chondrosarcoma. Inhibitors of the IDH1 and IDH2 mutation and LSD1-expressing appear to have potential as a possible therapy of chondrosarcoma. However, as we look forward to the future, questions can be laid emphasis on searching a representative marker of chromosomal gene mutation in chondrosarcoma.
Although surgical resection is up to now the only curative approach to malignant chondrosarcoma, increasing studies provide important information, and hopefully new, effective therapies that IHH and PTHrP signaling pathways are essential for balance of bone development and may be potentially associated with tumor development and progression of chondrosarcoma. Besides, there are a number of environmentally herbal medicines or alternative compounds able to induce tumor apoptosis, although these studies on the grade of the cell lines or the specimens are obscure and difficult. Therefore, if we further determine whether these compounds are suitable for the next clinical trial and the targeted treatment, one of them can be developed as a new therapeutic treatment in chondrosarcoma.
In addition, treatment of agents targeting the angiogenesis in soft tissue sarcoma is currently underway that regulation of endothelin-1, potent vasoconstrictor, expression in chondrosarcoma, for instance, involves a physiologic response to tumor angiogenesis and metastasis [127]. As chondrosarcoma vascularity can be extended by enhancing cartilage angiogenesis to promote drug delivery, stimulating vascular endothelial growth factor (VEGF) production in the late stage may be regarded as a possible approach to inhibit tumor progression. The most promising approach for the treatment of human chondrosarcoma that is currently available 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523
includes a combination of experimental therapeutic options and sufficiently surgical resection. Ultimately, future studies should further confirm these therapeutic options based on their experimental characteristics to determine whether they are suitable for the next clinical trial and targeted treatment of one or more subtypes of chondrosarcoma. Fortunately, the increasing study of this disease is providing more important information about chondrosarcoma therapies, and promising developments concerning tumor angiogenesis could probably diminish the side effects for surgical interventions, thus improving the quality of life of patients with chondrosarcoma. For those reasons, we believe that a new and effective therapy will be developed in the near future.
Declaration of interest
This work was supported by grants from the National Science Council of Taiwan (NSC100-2320-B-039-028-MY3 and NSC101-2314-B-039-002-MY3). The authors declare no conflict of interest and have received no payment in preparation of this manuscript.
Bibliography
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
1. Kaste, S.C., Imaging pediatric bone sarcomas. Radiol Clin North Am 2011; 49(4): 749-65, vi-vii.
2. Gelderblom, H., P.C. Hogendoorn, S.D. Dijkstra, et al., The clinical approach towards chondrosarcoma. Oncologist 2008; 13(3): 320-9.
• This review provides an overview of the histopathology, classification, diagnostic procedures, and therapies of chondrosarcoma.
3. Douis, H. and A. Saifuddin, The imaging of cartilaginous bone tumours. II. Chondrosarcoma. Skeletal Radiol 2013; 42(5): 611-26.
4. Clark, J.C., C.R. Dass, and P.F. Choong, Development of chondrosarcoma animal models for assessment of adjuvant therapy. ANZ J Surg 2009; 79(5):
327-36.
5. Baek, H.J., S.J. Lee, K.H. Cho, et al., Subungual tumors: clinicopathologic correlation with US and MR imaging findings. Radiographics 2010; 30(6): 1621-36.
6. Douis, H. and A. Saifuddin, The imaging of cartilaginous bone tumours. I. Benign lesions. Skeletal Radiol 2012; 41(10): 1195-212.
7. Ho, Y.Y. and J. Choueka, Synovial chondromatosis of the upper extremity. J Hand Surg Am 2013; 38(4): 804-10.
8. Pansuriya, T.C., H.M. Kroon, and J.V. Bovee, Enchondromatosis: insights 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564
on the different subtypes. Int J Clin Exp Pathol 2010; 3(6): 557-69.
9. Ho, L., A. Stojanovski, H. Whetstone, et al., Gli2 and p53 cooperate to regulate IGFBP-3- mediated chondrocyte apoptosis in the progression from benign to malignant cartilage tumors. Cancer Cell 2009; 16(2): 126-36.
• This is about malignant transformation of chondrosarcoma.
10. Schmale, G.A., D.S. Hawkins, J. Rutledge, et al., Malignant progression in two children with multiple osteochondromas. Sarcoma 2010; 2010: 417105. 11. Rosenberg, A.E., WHO Classification of Soft Tissue and Bone, fourth
edition: summary and commentary. Curr Opin Oncol 2013; 25(5): 571-3.
• Evidence-based guidelines for chondrosarcoma.
12. Hameed, M. and H. Dorfman, Primary malignant bone tumors--recent developments. Semin Diagn Pathol 2011; 28(1): 86-101.
13. Unni, K.K. and D.C. Dahlin, Dahlin's bone tumors : general aspects and
data on 11,087 cases. 5th ed. 1996, Philadelphia: Lippincott-Raven. 463.
14. Chow, W.A., Update on chondrosarcomas. Curr Opin Oncol 2007; 19(4): 371-6.
15. Murphey, M.D., E.A. Walker, A.J. Wilson, et al., From the archives of the AFIP: imaging of primary chondrosarcoma: radiologic-pathologic correlation. Radiographics 2003; 23(5): 1245-78.
16. Wootton-Gorges, S.L., MR imaging of primary bone tumors and tumor-like conditions in children. Magn Reson Imaging Clin N Am 2009; 17(3): 469-87, vi.
17. Dähnert, W., Radiology review manual. Seventh Edition. ed. 2011, Philadelphia: Wolters Kluwer Health/Lippincott Williams Wilkins. xxix, 1227 pages.
18. Soldatos, T., E.F. McCarthy, S. Attar, et al., Imaging features of chondrosarcoma. J Comput Assist Tomogr 2011; 35(4): 504-11.
19. Pritchard, D.J., R.J. Lunke, W.F. Taylor, et al., Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer 1980; 45(1): 149-57. 20. Littrell, L.A., D.E. Wenger, L.E. Wold, et al., Radiographic, CT, and MR
imaging features of dedifferentiated chondrosarcomas: a retrospective review of 174 de novo cases. Radiographics 2004; 24(5): 1397-409.
21. Grimer, R.J., G. Gosheger, A. Taminiau, et al., Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group.
Eur J Cancer 2007; 43(14): 2060-5.
22. Unni, K.K., D.C. Dahlin, J.W. Beabout, et al., Chondrosarcoma: clear-cell variant. A report of sixteen cases. J Bone Joint Surg Am 1976; 58(5): 676-83.
23. Collins, M.S., T. Koyama, R.G. Swee, et al., Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation. Skeletal Radiol 2003; 32(12): 687-94. 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606
24. Itala, A., T. Leerapun, C. Inwards, et al., An institutional review of clear cell chondrosarcoma. Clin Orthop Relat Res 2005; 440: 209-12.
25. Lightenstein, L. and D. Bernstein, Unusual benign and malignant chondroid tumors of bone. A survey of some mesenchymal cartilage tumors and malignant chondroblastic tumors, including a few multicentric ones, as well as many atypical benign chondroblastomas and chondromyxoid fibromas.
Cancer 1959; 12: 1142-57.
26. Wehrli, B.M., W. Huang, B. De Crombrugghe, et al., Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma
from other small blue round cell tumors. Hum Pathol 2003; 34(3): 263-9. 27. Vencio, E.F., C.M. Reeve, K.K. Unni, et al., Mesenchymal chondrosarcoma
of the jaw bones: clinicopathologic study of 19 cases. Cancer 1998; 82(12): 2350-5.
28. Damron, T.A., W.G. Ward, and A. Stewart, Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report.
Clin Orthop Relat Res 2007; 459: 40-7.
29. Bloch, O.G., B.J. Jian, I. Yang, et al., A systematic review of intracranial chondrosarcoma and survival. J Clin Neurosci 2009; 16(12): 1547-51. 30. Chen, K.Y. and C.H. Yao, Repair of bone defects with gelatin-based
composites: A review. Biomedicine 2011; 1( 1): 29-32.
31. Hsu, S.C. and J.G. Chung, Anticancer potential of emodin. Biomedicine 2012; 2(3): 108-116.
32. Kobayashi, T., U.I. Chung, E. Schipani, et al., PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Development 2002; 129(12): 2977-86.
33. Tiet, T.D., S. Hopyan, P. Nadesan, et al., Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol 2006;
168(1): 321-30.
34. Ng, J.M. and T. Curran, The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer 2011; 11(7): 493-501.
35. Lorusso, P.M., A. Jimeno, G. Dy, et al., Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17(17): 5774-82.
36. Sandhiya, S., G. Melvin, S.S. Kumar, et al., The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother 2013; 4(1): 4-7.
37. Babacan, T., F. Sarici, and K. Altundag, Vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 367(10): 969-70; author reply 970.
38. Hopyan, S., P. Nadesan, C. Yu, et al., Dysregulation of hedgehog signalling predisposes to synovial chondromatosis. J Pathol 2005; 206(2): 143-50. 39. Rozeman, L.B., L. Hameetman, A.M. Cleton-Jansen, et al., Absence of IHH
and retention of PTHrP signalling in enchondromas and central 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648
chondrosarcomas. J Pathol 2005; 205(4): 476-82.
40. van Oosterwijk, J.G., D. Meijer, M.A. van Ruler, et al., Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFbeta as potential
targets. Am J Pathol 2013; 182(4): 1347-56.
41. Zhang, Y.X., J.G. van Oosterwijk, E. Sicinska, et al., Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res 2013; 19(14): 3796-807.
42. van Oosterwijk, J.G., M.A. van Ruler, I.H. Briaire-de Bruijn, et al., Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells. Br J Cancer 2013; 109(5):
1214-22.
43. Schrage, Y.M., I.H. Briaire-de Bruijn, N.F. de Miranda, et al., Kinome profiling of chondrosarcoma reveals SRC-pathway activity and dasatinib as option for treatment. Cancer Res 2009; 69(15): 6216-22.
44. El Rashedy, A.A. and H.Y. Aboul-Enein, Benzimidazole derivatives as potential anticancer agents. Mini Rev Med Chem 2013; 13(3): 399-407. 45. Liu, J.F., Y.L. Huang, W.H. Yang, et al., 1-Benzyl-2-Phenylbenzimidazole
(BPB), a Benzimidazole Derivative, Induces Cell Apoptosis in Human Chondrosarcoma through Intrinsic and Extrinsic Pathways. Int J Mol Sci 2012; 13(12): 16472-88.
46. Grutter, M.G., Caspases: key players in programmed cell death. Curr Opin Struct Biol 2000; 10(6): 649-55.
47. Liu, J.F., C.S. Chang, Y.C. Fong, et al., FPipTB, a benzimidazole derivative, induces chondrosarcoma cell apoptosis via endoplasmic reticulum stress and apoptosis signal-regulating kinase 1. Mol Carcinog
2011: published online 18 May 2011, doi: 10.1002/mc.20787
48. Feldman, D.E., V. Chauhan, and A.C. Koong, The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res 2005; 3(11): 597-605.
49. Moenner, M., O. Pluquet, M. Bouchecareilh, et al., Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 2007; 67(22): 10631-4. 50. Li, T.M., T.Y. Lin, S.F. Hsu, et al., The novel benzimidazole derivative,
MPTB, induces cell apoptosis in human chondrosarcoma cells. Mol Carcinog 2011; 50(10): 791-803.
51. Alnemri, E.S., D.J. Livingston, D.W. Nicholson, et al., Human ICE/CED-3 protease nomenclature. Cell 1996; 87(2): 171.
52. Brenner, D. and T.W. Mak, Mitochondrial cell death effectors. Curr Opin Cell Biol 2009; 21(6): 871-7.
53. Zhang, Y., M. Luo, Y. Zu, et al., Dryofragin, a phloroglucinol derivative, induces apoptosis in human breast cancer MCF-7 cells through ROS-649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690
mediated mitochondrial pathway. Chem Biol Interact 2012; 199(2): 129-36. 54. Ito, H., T. Muranaka, K. Mori, et al., Ichthyotoxic phloroglucinol derivatives from Dryopteris fragrans and their anti-tumor promoting activity. Chem Pharm Bull (Tokyo) 2000; 48(8): 1190-5.
55. Liu, J.F., W.H. Yang, Y.C. Fong, et al., BFPP, a phloroglucinol derivative, induces cell apoptosis in human chondrosarcoma cells through endoplasmic
reticulum stress. Biochem Pharmacol 2010; 79(10): 1410-7.
56. Bradbury, D.A., T.D. Simmons, K.J. Slater, et al., Measurement of the ADP:ATP ratio in human leukaemic cell lines can be used as an indicator of cell viability, necrosis and apoptosis. J Immunol Methods 2000; 240(1-2): 79-92.
57. Feig, D.I., T.M. Reid, and L.A. Loeb, Reactive oxygen species in tumorigenesis. Cancer Res 1994; 54(7 Suppl): 1890s-1894s.
58. Schumacker, P.T., Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 2006; 10(3): 175-6.
59. Chen, S.Y., C.L. Zhang, Y.Z. Chen, et al., Trichodermin (4beta-acet-oxy-12,13-epoxy-trichothec-9-ene). Acta Crystallogr Sect E Struct Rep Online 2008; 64(Pt 4): o702.
60. Wang, L.W., B.G. Xu, J.Y. Wang, et al., Bioactive metabolites from Phoma species, an endophytic fungus from the Chinese medicinal plant Arisaema erubescens. Appl Microbiol Biotechnol 2012; 93(3): 1231-9.
61. Xu, X., J. Cheng, Y. Zhou, et al., Synthesis and antifungal activities of trichodermin derivatives as fungicides on rice. Chem Biodivers 2013; 10(4):
600-11.
62. Tijerino, A., R. Hermosa, R.E. Cardoza, et al., Overexpression of the Trichoderma brevicompactum tri5 gene: effect on the expression of the trichodermin biosynthetic genes and on tomato seedlings. Toxins (Basel) 2011; 3(9): 1220-32.
63. Kralj, A., M. Gurgui, G.M. Konig, et al., Trichothecenes induce accumulation of glucosylceramide in neural cells by interfering with lactosylceramide synthase activity. Toxicol Appl Pharmacol 2007; 225(1): 113-22.
64. Su, C.M., S.W. Wang, T.H. Lee, et al., Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells. Toxicol Appl Pharmacol 2013; 272(2): 335-44.
65. Fujiki, H., Green tea: Health benefits as cancer preventive for humans. Chem Rec 2005; 5(3): 119-32.
66. Shimizu, M. and I.B. Weinstein, Modulation of signal transduction by tea catechins and related phytochemicals. Mutat Res 2005; 591(1-2): 147-60. 67. Islam, S., N. Islam, T. Kermode, et al., Involvement of caspase-3 in
epigallocatechin-3-gallate-mediated apoptosis of human chondrosarcoma 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732
cells. Biochem Biophys Res Commun 2000; 270(3): 793-7.
68. Tang, G.Q., T.Q. Yan, W. Guo, et al., (-)-Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells. J Cancer Res Clin Oncol 2010; 136(8): 1179-85.
69. Yang, W.H., Y.C. Fong, C.Y. Lee, et al., Epigallocatechin-3-gallate induces cell apoptosis of human chondrosarcoma cells through apoptosis
signal-regulating kinase 1 pathway. J Cell Biochem 2011; 112(6): 1601-11.
70. Zhang, Q., L. Cai, G. Zhong, et al., [Simultaneous determination of jatrorrhizine, palmatine, berberine, and obacunone in Phellodendri Amurensis Cortex by RP-HPLC]. Zhongguo Zhong Yao Za Zhi 2010; 35(16): 2061-4.
71. Tillhon, M., L.M. Guaman Ortiz, P. Lombardi, et al., Berberine: new perspectives for old remedies. Biochem Pharmacol 2012; 84(10): 1260-7. 72. Singh, T., M. Vaid, N. Katiyar, et al., Berberine, an isoquinoline alkaloid,
inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E(2) and prostaglandin E(2) receptors.
Carcinogenesis 2011; 32(1): 86-92.
73. Wu, C.M., T.M. Li, T.W. Tan, et al., Berberine Reduces the Metastasis of Chondrosarcoma by Modulating the alpha v beta 3 Integrin and the PKC delta , c-Src, and AP-1 Signaling Pathways. Evid Based Complement Alternat Med 2013; 2013: 423164.
74. Stupack, D.G., The biology of integrins. Oncology (Williston Park) 2007; 21(9 Suppl 3): 6-12.
75. Missan, D.S. and M. DiPersio, Integrin control of tumor invasion. Crit Rev Eukaryot Gene Expr 2012; 22(4): 309-24.
76. Chattopadhyay, I., U. Bandyopadhyay, K. Biswas, et al., Indomethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen. Free Radic Biol Med 2006; 40(8): 1397-408.
77. Aggarwal, B.B., C. Sundaram, N. Malani, et al., Curcumin: the Indian solid gold. Adv Exp Med Biol 2007; 595: 1-75.
78. Wilken, R., M.S. Veena, M.B. Wang, et al., Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell
carcinoma. Mol Cancer 2011; 10: 12.
79. Lin, H.J., C.C. Su, H.F. Lu, et al., Curcumin blocks migration and invasion of mouse-rat hybrid retina ganglion cells (N18) through the inhibition of MMP-2, -9, FAK, Rho A and Rock-1 gene expression. Oncol Rep 2010; 23(3): 665-70.
80. Lin, S.S., K.C. Lai, S.C. Hsu, et al., Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774
metalloproteinase-2 and -9 and Vascular Endothelial Growth Factor (VEGF). Cancer Lett 2009; 285(2): 127-33.
81. Yallapu, M.M., D.M. Maher, V. Sundram, et al., Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth. J Ovarian Res 2010; 3: 11. 82. Shehzad, A., J. Lee, and Y.S. Lee, Curcumin in various cancers. Biofactors
2013; 39(1): 56-68.
83. Lee, H.P., T.M. Li, J.Y. Tsao, et al., Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway. Int Immunopharmacol 2012; 13(2): 163-9.
84. Bovee, J.V., P.C. Hogendoorn, J.S. Wunder, et al., Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer 2010; 10(7): 481-8.
• This review is the about genetic therapy of chondrosarcomas.
85. Oda, Y. and M. Tsuneyoshi, Extrarenal rhabdoid tumors of soft tissue: clinicopathological and molecular genetic review and distinction from other soft-tissue sarcomas with rhabdoid features. Pathol Int 2006; 56(6): 287-95. 86. Lin, C., P.A. Meitner, and R.M. Terek, PTEN mutation is rare in
chondrosarcoma. Diagn Mol Pathol 2002; 11(1): 22-6.
87. Rozeman, L.B., K. Szuhai, Y.M. Schrage, et al., Array-comparative genomic hybridization of central chondrosarcoma: identification of ribosomal protein S6 and cyclin-dependent kinase 4 as candidate target genes for genomic aberrations. Cancer 2006; 107(2): 380-8.
88. Terek, R.M., J.H. Healey, P. Garin-Chesa, et al., p53 mutations in chondrosarcoma. Diagn Mol Pathol 1998; 7(1): 51-6.
89. Schrage, Y.M., S. Lam, A.G. Jochemsen, et al., Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol
Med 2009; 13(9A): 2843-52.
90. van Beerendonk, H.M., L.B. Rozeman, A.H. Taminiau, et al., Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression. J Pathol 2004; 202(3): 359-66.
91. Asp, J., L. Sangiorgi, S.E. Inerot, et al., Changes of the p16 gene but not the p53 gene in human chondrosarcoma tissues. Int J Cancer 2000; 85(6): 782-6.
92. Larramendy, M.L., M. Tarkkanen, J. Valle, et al., Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic
hybridization in chondrosarcomas. Am J Pathol 1997; 150(2): 685-91. 93. Bovee, J.V., R. Sciot, P. Dal Cin, et al., Chromosome 9 alterations and
trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes. Diagn Mol Pathol 2001; 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816
10(4): 228-35.
94. Amary, M.F., K. Bacsi, F. Maggiani, et al., IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011; 224(3): 334-43.
95. Corpas, F.J., J.B. Barroso, L.M. Sandalio, et al., Peroxisomal NADP-Dependent Isocitrate Dehydrogenase. Characterization and Activity Regulation during Natural Senescence. Plant Physiol 1999; 121(3): 921-928.
96. Losman, J.A. and W.G. Kaelin, Jr., What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 2013; 27(8):
836-52.
97. Yan, H., D.W. Parsons, G. Jin, et al., IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765-73.
98. Sasaki, M., C.B. Knobbe, M. Itsumi, et al., D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane
function. Genes Dev 2012; 26(18): 2038-49.
99. Pansuriya, T.C., R. van Eijk, P. d'Adamo, et al., Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011; 43(12): 1256-61.
100. Rohle, D., J. Popovici-Muller, N. Palaskas, et al., An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340(6132): 626-30.
101. Wang, F., J. Travins, B. DeLaBarre, et al., Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013;
340(6132): 622-6.
102. Lu, C., P.S. Ward, G.S. Kapoor, et al., IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483(7390): 474-8.
103. Kerr, D.A., H.U. Lopez, V. Deshpande, et al., Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations. Am J Surg Pathol 2013; 37(6): 787-95.
104. Thiery, J.P., H. Acloque, R.Y. Huang, et al., Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139(5): 871-90.
105. van Oosterwijk, J.G., J.K. Anninga, H. Gelderblom, et al., Update on targets and novel treatment options for high-grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am 2013; 27(5): 1021-48.
• This review discusses the pathologic features and current targets being validated in the clinic.
106. Guo, Y., X. Zi, Z. Koontz, et al., Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858
met and metalloproteinases in osteosarcoma Saos-2 cells. J Orthop Res 2007; 25(7): 964-71.
107. Shang, Y., Z. Li, H. Li, et al., TIM-3 expression in human osteosarcoma: Correlation with the expression of epithelial-mesenchymal
transition-specific biomarkers. Oncol Lett 2013; 6(2): 490-494.
108. Shi, Y., F. Lan, C. Matson, et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119(7): 941-53.
109. Hayami, S., J.D. Kelly, H.S. Cho, et al., Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer 2011; 128(3): 574-86.
110. Bennani-Baiti, I.M., I. Machado, A. Llombart-Bosch, et al., Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol 2012; 43(8): 1300-7.
111. Dai, X., W. Ma, X. He, et al., Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing's sarcoma. Med Sci Monit 2011; 17(8): RA177-190.
•• This review is about therapeutic strategies for chondrosarcoma
112. Yuan, X.W., X.F. Zhu, X.F. Huang, et al., Interferon-alpha enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. Acta Pharmacol Sin 2007; 28(11): 1835-41.
113. Verhoef, C., J.H. de Wilt, D.J. Grunhagen, et al., Isolated limb perfusion with melphalan and TNF-alpha in the treatment of extremity sarcoma. Curr Treat Options Oncol 2007; 8(6): 417-27.
114. Wang, Y., D. Mandal, S. Wang, et al., Platelet-derived growth factor receptor beta inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity: imatinib and TRAIL dual therapy.
Cancer 2010; 116(16): 3892-902.
115. Pollack, S.M., Y. Li, M.J. Blaisdell, et al., NYESO-1/LAGE-1s and PRAME are targets for antigen specific T cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine. PLoS One 2012; 7(2):
e32165.
116. Schwab, J.H., P.J. Boland, N.P. Agaram, et al., Chordoma and chondrosarcoma gene profile: implications for immunotherapy. Cancer Immunol Immunother 2009; 58(3): 339-49.
117. Radons, J., W. Falk, and T.E. Schubert, Interleukin-10 does not affect IL-1-induced interleukin-6 and metalloproteinase production in human
chondrosarcoma cells, SW1353. Int J Mol Med 2006; 17(2): 377-83.
118. Pedersen, B.K. and M.A. Febbraio, Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88(4): 1379-406.
119. Rose-John, S., J. Scheller, G. Elson, et al., Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900
inflammation and cancer. J Leukoc Biol 2006; 80(2): 227-36.
120. Culig, Z., H. Steiner, G. Bartsch, et al., Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem 2005; 95(3): 497-505.
121. Tzeng, H.E., C.H. Tsai, Z.L. Chang, et al., Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Biochem Pharmacol 2013; 85(4): 531-40.
122. Tan, T.W., W.H. Yang, Y.T. Lin, et al., Cyr61 increases migration and MMP-13 expression via alphavbeta3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells. Carcinogenesis 2009; 30(2): 258-68.
123. Hou, C.H., Y.C. Hsiao, Y.C. Fong, et al., Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. Bone 2009; 44(2): 233-42.
124. Egeblad, M. and Z. Werb, New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2(3): 161-74.
125. Kerkela, E. and U. Saarialho-Kere, Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol
2003; 12(2): 109-25.
126. Tang, C.H., C.F. Chen, W.M. Chen, et al., IL-6 increases MMP-13 expression and motility in human chondrosarcoma cells. J Biol Chem 2011; 286(13): 11056-66.
127. Wu, M.H., C.Y. Huang, J.A. Lin, et al., Endothelin-1 promotes vascular endothelial growth factor-dependent angiogenesis in human chondrosarcoma cells. Oncogene 2013: published 15 April 2013, doi:
10.1038/onc.2013.109 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928
