Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process of bone metastasis, the roles of the Wnt signaling, and the available experimental models and treatments.
Animals ; Bone Neoplasms ; drug therapy ; metabolism ; radiotherapy ; secondary ; surgery ; Breast Neoplasms ; metabolism ; pathology ; Disease Models, Animal ; Drug Delivery Systems ; Female ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Male ; Mice ; Prostatic Neoplasms ; metabolism ; pathology ; Wnt Proteins ; metabolism ; Wnt Signaling Pathway ; beta Catenin ; metabolism

OBJECTIVETo study the effect and mechanisms of quercetin (Qu) on proliferation and apoptosis of human methotrexate resistant osteosarcoma cell U-2OS/MTX300.

METHODMTT assay was used to observe cell proliferation. The apoptosis was examined by using Annexin V/PI staining. Western blot of mitochondrial membrane potential and cytochrome c were used to detect mitochondria spoptosis pathway. The protein expressions related to Akt pathway was detected by continuous activated Akt transient transfection and western blot.

RESULTQu can obviously inhibit the growth of human MTX resistant osteosarcoma cell U-2OS/MTX300 cells in a dose- and time-dependent manner. Annexin V/PI staining showed obvious cell apoptosis. Reduction of mitochondrial membrane potential, release of mitochondrial cytochrome c to cytosol and dephoshorylation of Akt were observed after Qu treatment.

CONCLUSIONQu can inhibit proliferation and induce apoptosis of human MTX resistant osteosarcoma cell U-2OS/MTX300, which may be related with mitochondrial apoptosis pathway and Akt activity.

Apoptosis ; drug effects ; Bone Neoplasms ; drug therapy ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Osteosarcoma ; drug therapy ; pathology ; Proto-Oncogene Proteins c-akt ; metabolism ; Quercetin ; pharmacology

OBJECTIVETo evaluate the clinical efficacy of zoledronic acid combined with chemotherapy in the management of skeletal metastasis of non-small cell lung cancer (NSCLC) and investigate the value in urine amino-terminal telopeptide of type I collagen (uNTX) and serum bone specific alkaline phosphatase (sBALP) in monitoring skeletal metastasis of NSCLC.

METHODSFrom February, 2007 to January, 2009, 32 NSCLC patients with bone metastases received treatment with zoledronic acid at the dose of 4 mg given every 3 weeks and platinum-based chemotherapy (each cycle lasting for 3 weeks). Before and during the treatments, uNTX and sBALP were measured in these patients using ELISA and precipitation with wheat germ lectin, respectively. The patients were followed up for skeletal-related events (SREs) and status of survival.

RESULTSA significant decrease occurred in the pain scores and analgesic use in the patients after the therapy. SREs were not observed during the treatment. Serum creatinine and calcium levels underwent no significant variation during the treatment. Eleven patients reported 14 possible zoledronic acid-related adverse events. The concentration of uNTX and sBALP in patients with bone metastases was above the upper limit of the normal range. A positive correlation was observed between the levels of the markers and the extent of bone metastases. At the third month, uNTX and sBALP were significantly lowered, but radionuclide whole-body bone imaging showed no obvious changes. Of the 32 patients, 24 had elevated uNTX values, which became normal after the treatment in 15 patients and remained elevated in the other 9 patients. SREs occurred in these two subgroups at the rates of 53% and 89% (P=0.039), respectively. Twenty-six patients had elevated sBALP level, and 16 of them exhibited normal sBALP level after the treatment. The incidences of SREs in the patients with elevated and normal sBALP level were 50% and 90% (P=0.038), respectively. The levels of uNTX/Cr and sBALP were not correlated to the survival of the patients.

CONCLUSIONSZoledronic acid combined with chemotherapy is an effective treatment for NSCLC with bone metastases. Zoledronic acid is safe and well tolerated. Urinary NTX and serum BALP have a high value in the diagnosis, therapeutic effect monitoring and SRE prediction of NSCLC with bone metastases.

Adult ; Aged ; Alkaline Phosphatase ; blood ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Biomarkers, Tumor ; metabolism ; Bone Density Conservation Agents ; therapeutic use ; Bone Neoplasms ; drug therapy ; metabolism ; secondary ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; metabolism ; pathology ; Collagen Type I ; urine ; Diphosphonates ; therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; Imidazoles ; therapeutic use ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Male ; Middle Aged ; Peptides ; urine

OBJECTIVEThe aim of this study was to access the relationship of osteolytic bone metabolic markers such as serum type I collagen carboxy-terminal telopeptide (sICTP), N-terminal cross-linked telopeptides of type I collagen (uNTx), urinary pyridinoline (uPyd) with the therapeutic effect in breast cancer patients with bone metastases.

METHODS120 patients with breast cancer were included in this study. The levels of sICTP, uNTx and uPYD were measured by ELISA assay. The differences were compared between patients with and without bone metastasis. The patients with bone metastasis were treated and followed up as clinically indicated.

RESULTSThe levels of all above mentioned biomarkers in patients with bone metastasis were significantly higher than that in patients without bone metastasis (P < 0.01). A significant correlation was found between each two markers (r > 0.5, P < 0.01). The biomarkers were examined again in 45 patients with bone metastasis after treatment to evaluate the treatment response. The median follow-up was 10 months. Based on clinical evaluation criteria, 25 patients were responders and 20 were non-responders. For responders, after 3 months treatment, the levels of the three bone markers were significantly reduced (P = 0.025, P < 0.001, P < 0.001). But for non-responders, with progression of bone lesions, the levels of the three markers were significantly raised (P = 0.011, P = 0.002, P = 0.002). By means of multiple logistic regression with stepwise selection, the uPyd and uNTx activities were closely correlated with treatment response (OR = 17.0, P = 0.019; OR = 16.7, P = 0.015), however, the sICTP did not show any correlation with treatment response P = 0.841).

CONCLUSIONThe levels of sICTP, uNTx and uPyd may be used as indicators in assessment of the effect of antiresorptive treatment and evaluation of prognosis in breast cancer patient with bone metastases.

Adult ; Aged ; Amino Acids ; urine ; Biomarkers, Tumor ; metabolism ; Bone Neoplasms ; drug therapy ; metabolism ; secondary ; Breast Neoplasms ; drug therapy ; metabolism ; pathology ; Collagen ; urine ; Collagen Type I ; blood ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Middle Aged ; Peptides ; blood ; Remission Induction

[Strengthening body resistance and archaeus herbs are those medicines used on asthenia syndrome of tumor, which can harmonize yin and yang, replenish deficiency of qi and blood, and improve entrails function, enhance physical capacity, and improve immunity function. They are intimate manifestation of strengthening body resistance and archaeus method on clinic. Study shows that strengthening body resistance and archaeus herbs have many effects, such as improving and adjusting immunity function, protecting bone marrow, improving haematogenesis function, raising digest and absorb function, improving substance metabolism, preventing gene mutation, inhibiting tumor cell proliferation, inducing tumor cell differentiation or apoptosis, resisting tumor invasion and metastasis, inhibiting formation of tumor vessel and activity of telomerase, etc. It's possibly the result of synergistic effect by multi-pathway and multi-target. Because strengthening body resistance and archaeus herbs are of variety and different herbs have different specificity, further research is needed to reveal the precise mechanism of them.
Apoptosis ; drug effects ; Bone Marrow ; drug effects ; Cell Differentiation ; drug effects ; Cell Proliferation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Enzyme Activation ; drug effects ; Neoplasms ; drug therapy ; metabolism ; pathology ; Telomerase ; metabolism

OBJECTIVETo study the histogenesis of giant cell tumor (GCT) and factors related to tumor recurrence, invasiveness and malignant transformation.

METHODSThe clinical features, radiologic classification, surgical approach, pathologic findings, immunophenotypes and follow-up data of 123 cases of GCT were analyzed.

RESULTSThere was a significant correlation between tumor recurrence and radiographic classification (P = 0.032), over-expression of CD147 (P = 0.034) and p53 (P = 0.005), and surgical approach (P = 0.0048) in GCT. The biologic behavior showed no correlation with intramedullary infiltration, cortical bone involvement, parosteal soft tissue extension, tumor thrombi, fusiform changes of mononuclear tumor cells, mitotic count, Ki-67 index, coagulative tumor necrosis, secondary aneurysmal bone cyst formation, and adjoining bony reaction. The positive rate of p63 in stromal cells of GCT (79.7%, 94/118) was significantly higher than that in chondroblastoma (44.7%, 21/47), osteosarcoma (22.2%, 10/45) and other giant cell-rich tumors.

CONCLUSIONSGCT is a bone tumor of low malignant potential. It is sometimes characterized by locally invasive growth, active proliferation, coagulative necrosis, secondary aneurysmal bone cyst and surrounding bony reaction. It is difficult to predict the biologic behavior of GCT. Over-expression of p53 in the tumor cells and CD147 in all components of GCT correlate with tumor invasiveness, recurrence and malignant transformation. Selection of suitable surgical approach with reference to radiologic classification is considered as an important factor in reducing the recurrence rate.

Adolescent ; Adult ; Aged ; Basigin ; metabolism ; Bone Neoplasms ; diagnostic imaging ; drug therapy ; metabolism ; pathology ; surgery ; Chemotherapy, Adjuvant ; Female ; Follow-Up Studies ; Giant Cell Tumor of Bone ; diagnostic imaging ; drug therapy ; metabolism ; pathology ; surgery ; Humans ; Male ; Membrane Proteins ; metabolism ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local ; Osteosarcoma ; pathology ; Phosphoglucomutase ; metabolism ; Radiography ; Tumor Suppressor Protein p53 ; metabolism ; Young Adult

OBJECTIVETo study the clinicopathologic and radiologic features of dedifferentiated chondrosarcoma, focusing on its diagnosis and differential diagnosis.

METHODClinical, radiological and pathologic findings of 14 cases of dedifferentiated chondrosarcoma (including biopsy and surgical specimens) were analyzed by hematoxylin and eosin stained sections and immunohistochemistry.

RESULTSThe mean age of patients was 52 years. The male-to-female ratio was 9:5. The most common sites of involvement were pelvis, femur and humerus, similar to the conventional chondrosarcoma. Radiologically, they were malignant tumors with dimorphic pattern. Grossly, central chondrosarcomas were more common than those of the peripheral. An essential histological feature of dedifferentiated chondrosarcoma was an abrupt interface between the low-grade cartilaginous tumor and high-grade anaplastic sarcoma. The most common dedifferentiated components were osteosarcoma, malignant fibrous histocytoma and fibrosarcoma. False negative diagnosis and erroneous diagnosis were frequent when only one-time biopsy was available.

CONCLUSIONSDedifferentiated chondrosarcoma is a rare subtype of chondrosarcoma with poor prognosis, which has different features of clinical manifestation, imaging features and pathological characteristics, compared to conventional chondrosarcoma and chondroblastic osteosarcoma.

Adult ; Aged ; Bone Neoplasms ; diagnostic imaging ; drug therapy ; pathology ; surgery ; Cell Differentiation ; Chondrosarcoma ; diagnostic imaging ; drug therapy ; pathology ; surgery ; Chondrosarcoma, Mesenchymal ; pathology ; Diagnosis, Differential ; Female ; Femoral Neoplasms ; diagnostic imaging ; drug therapy ; pathology ; surgery ; Follow-Up Studies ; Humans ; Humerus ; pathology ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Osteosarcoma ; pathology ; Pelvic Bones ; pathology ; Radiography ; Vimentin ; metabolism ; Young Adult

OBJECTIVETo evaluate the efficacy and adverse reactions of Herceptin as a single agent in patients with HER2 overexpressing metastatic breast cancer.

METHODSThere were two kinds of therapy protocol. One was loading-dose of 4 mg/kg intravenously, followed by a 2 mg/kg maintenance dose of weekly intervals. The other was loading-dose of 8 mg/kg, followed by 6 mg/kg of every three weeks intervals.

RESULTSAmong 20 patients with evaluated efficacy, there was no complete response, 5 patients (25.0%) showed partial response (PR), 5 (25.0%) stable disease (SD) and 10 (50.0%) progressive disease (PD). Of 22 patients, the overall response rate was 22.7%. The median time of disease progression and treatment failure was 6 weeks and 6.5 weeks, respectively. The most common adverse reactions were fever and chill. Cardiac symptoms could be seen in some patients.

CONCLUSIONHerceptin is an active agent for the patients with HER2 overexpressing metastatic breast cancer and the adverse events are well tolerated.

Adult ; Aged ; Antibodies, Monoclonal ; administration & dosage ; adverse effects ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; administration & dosage ; adverse effects ; Bone Neoplasms ; drug therapy ; secondary ; Breast Neoplasms ; drug therapy ; metabolism ; pathology ; Disease Progression ; Disease-Free Survival ; Drug Administration Schedule ; Female ; Fever ; chemically induced ; Heart Diseases ; chemically induced ; Humans ; Middle Aged ; Neoplasm Recurrence, Local ; drug therapy ; metabolism ; Receptor, ErbB-2 ; metabolism ; Soft Tissue Neoplasms ; drug therapy ; secondary ; Trastuzumab

Metastasis represents by far the most feared complication of prostate carcinoma and is the main cause of death for patients. The skeleton is frequently targeted by disseminated cancer cells and represents the sole site of spread in more than 80% of prostate cancer cases. Compatibility between select malignant phenotypes and the microenvironment of colonized tissues is broadly recognized as the culprit for the organ-tropism of cancer cells. Here, we review our recent studies showing that the expression of platelet-derived growth factor receptor alpha (PDGFRα) supports the survival and growth of prostate cancer cells in the skeleton and that the soluble fraction of bone marrow activates PDGFRα in a ligand-independent fashion. Finally, we offer pre-clinical evidence that this receptor is a viable target for therapy.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Bone Marrow ; enzymology ; pathology ; Bone Neoplasms ; prevention & control ; secondary ; Enzyme Activation ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptor, Platelet-Derived Growth Factor alpha ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Signal Transduction ; Transcriptional Activation

Chemotherapy plays an important role in the treatment of metastatic breast cancer. It is important to monitor chemotherapeutic efficacy, to find a simple and efficient tool to guide treatment, and to predict the efficacy of treatment in a timely and accurate manner. This study aimed to detect mucin-1 (MUC1)-positive circulating tumor cells and MUC1 protein in the peripheral blood of patients with metastatic breast cancer and to investigate their relationship to chemotherapeutic efficacy. MUC1 mRNA was detected in the peripheral blood of 34 patients with newly diagnosed metastatic breast cancer by reverse transcription-polymerase chain reaction. The positive rates of MUC1 mRNA were 88.2% before chemotherapy and 70.6% after chemotherapy, without a significant difference (P=0.564); MUC1 mRNA expression before chemotherapy had no correlation with treatment effectiveness (P=0.281). The response rate of MUC1 mRNA-negative patients after first-cycle chemotherapy was significantly higher (P=0.009) and the progression-free survival (PFS) was clearly longer than those of MUC1 mRNA-positive patients (P=0.095). MUC1 protein in peripheral blood plasma was detected by an ELISA competitive inhibition assay. The patients with decreased MUC1 protein after chemotherapy had a significantly longer PFS than those with elevated MUC1 protein (P=0.044). These results indicate that the outcomes of MUC1 mRNA-negative patients after chemotherapy are better than those of MUC1 mRNA-positive patients. In addition, patients with decreased expression of MUC1 protein have a better PFS.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Bone Neoplasms ; drug therapy ; secondary ; Breast Neoplasms ; drug therapy ; metabolism ; pathology ; Cell Line, Tumor ; Disease-Free Survival ; Female ; Humans ; Liver Neoplasms ; drug therapy ; secondary ; Lymphatic Metastasis ; Middle Aged ; Mucin-1 ; blood ; genetics ; metabolism ; Neoplastic Cells, Circulating ; metabolism ; RNA, Messenger ; metabolism ; Receptors, Progesterone ; metabolism ; Taxoids ; administration & dosage ; Thiotepa ; administration & dosage