The development of cancer is a multistep and complex process involving interactions between tumor cells and the tumor microenvironment (TME). C-X-C chemokine ligand 13 (CXCL13) and its receptor, CXCR5, make crucial contributions to this process by triggering intracellular signaling cascades in malignant cells and modulating the sophisticated TME in an autocrine or paracrine fashion. The CXCL13/CXCR5 axis has a dominant role in B cell recruitment and tertiary lymphoid structure formation, which activate immune responses against some tumors. In most cancer types, the CXCL13/CXCR5 axis mediates pro-neoplastic immune reactions by recruiting suppressive immune cells into tumor tissues. Tobacco smoke and haze (smohaze) and the carcinogen benzo(a)pyrene induce the secretion of CXCL13 by lung epithelial cells, which contributes to environmental lung carcinogenesis. Interestingly, the knockout of CXCL13 inhibits benzo(a)pyrene-induced lung cancer and azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Thus, a better understanding of the context-dependent functions of the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of agents targeting this axis in different malignant tumors.

Total knee arthroplasty (TKA) has been reported to be the most successful treatment for patients with advanced osteoarthritis, however, early postoperative pain has become an unresolved issue. The aim of this Meta-analysis is to evaluate the efficacy and safety of steroid addition to multimodal cocktail periarticular injection (MCPI) in patients undergoing TKA. Clinical randomized controlled trials concerning the efficacy and safety of MCPI containing steroids in TKA published up to December 2014 were retrieved from PubMed, Cochrane library, EMbase databases. The methodological quality of the included studies was assessed by the 12-item scale. Data analysis was performed using StataSE12.0. Six randomized controlled trials involving a total of 567 patients were assessed; the steroid group included 305 patients, and the control group included 262 patients. The meta-analysis showed that MCPI with steroids in TKA significantly reduced postoperative pain; duration of time required to perform straight-leg raising and length of hospital stay was (P < 0.05). Neither the early postoperative nor the long-term range of motion of knee showed any statistical difference between the non-steroid and steroid group (P >0.05). For safety, steroids did not increase the incidence of postoperative infection and wound oozing (P >0.05); no tendon rupture was reported up to now. In addition, steroids did not decrease the postoperative drainage through the reduction of prostaglandins (P >0.05). For patients undergoing TKA, the addition of steroids to MCPI improved the analgesic effect and was proved to be highly safe. The duration of time required to perform straight-leg raising and length of hospital stay was significantly reduced. However, MCPI with steroids neither increased the early postoperative range of motion (ROM) or the long-term ROM of knee, nor did it reduce the postoperative drainage. However, the best results are acquired in patients without any altered immunological status.

Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.

Bone loss leading to aseptic loosening of the prosthesis and periprosthetic fracture is a mode of failure in cementless total hip arthroplasty (THA). The aim of this meta-analysis was to evaluate the effect of bisphosphonates in preventing femoral periprosthetic bone resorption following primary cementless THA zone by zone. Clinical randomized controlled trials concerning bisphosphonates application after primary cementless THA published up to October 2014 were retrieved from PubMed, Cochrane library, and Embase databases. The methodological quality of the included studies was assessed by the Physiotherapy Evidence Database (PEDro) scale. Data analysis was performed using StataSE12.0. Ten randomized controlled trials involving a total of 502 patients were assessed; the bisphosphonates group included 256 patients and the control group included 246 patients. The meta-analysis showed that the bone mineral density (BMD) of most femoral periprosthetic zones in bisphosphonates group was significantly higher than that in the control group at 3 months postoperatively except zone 5 with no significant difference. At 6 and 12 months, the BMD of bisphosphonates group was much higher than that in control group except zone 5, which showed no statistical difference. The BMD of bisphosphonates group was persistently higher than control group in zone 6 and 7 at 5 years postoperatively, while the other zones had no significant difference. Both serum bone alkaline phosphatase and urinary type I collagen N-telopeptide were significantly suppressed by bisphosphonates at 3, 6, and 12 months. Bisphosphonates seem to decrease early femoral periprosthetic bone resorption after primary cementless THA. Drug efficacy was found to be long-standing in the main load-bearing zones.

Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

Volatile organic compounds (VOCs) in urine are potential biomarkers of breast cancer. Previously, our group has investigated breast cancer through analysis of VOCs in mouse urine and identified a panel of VOCs with the ability to monitor tumor progression. However, an unanswered question is whether VOCs can be exploited similarly to monitor the efficacy of antitumor treatments over time. Herein, subsets of tumor-bearing mice were treated with pitavastatin at high (8 mg/kg) and low (4 mg/kg) concentrations, and urine was analyzed through solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS). Previous investigations using X-ray and micro-CT analysis indicated pitavastatin administered at 8 mg/kg had a protective effect against mammary tumors, whereas 4 mg/kg treatments did not inhibit tumor-induced damage. VOCs from mice treated with pitavastatin were compared to the previously analyzed healthy controls and tumor-bearing mice using chemometric analyses, which revealed that mice treated with pitavastatin at high concentrations were significantly different than tumor-bearing untreated mice in the direction of healthy controls. Mice treated with low concentrations demonstrated significant differences relative to healthy controls and were reflective of tumor-bearing untreated mice. These results show that urinary VOCs can accurately and noninvasively predict the efficacy of pitavastatin treatments over time.