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TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
Inhibin-α deficiency is associated with testicular tumors, because inhibin and FSH levels are inversely related and FSH regulates the gonadal cell proliferation (89). Recently, transcriptome analysis studies in seminomas and of TCam-2 seminoma model cell line revealed the potentially active pathways. Combined datasets from Affymetrix microarrays and RNAseq analysis revealed the presence of transcript levels of TGF-β signaling. GDF3, GDF11 and BMP7 transcripts were consistently detected in seminomas and TCam-2. Transcripts encoding receptor proteins such as ACVR1A and ACVR1B, ACVR2A and ACVR2B were also detected at high levels (90).
Promising models for cancer-induced cachexia drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Tsuyoshi Suzuki, Stephan Von Haehling, Jochen Springer
Clinical studies have established gemcitabine as the standard treatment for advanced pancreatic cancer and have proven beneficial effects including improved survival from gemcitabine [101]. Unfortunately, there are serious side effects associated with gemcitabine therapy including cachexia. In a preclinical study, human SW1990 pancreatic cancer cells where implanted subcutaneously into nude mice followed by chemotherapy consisting of 50 mg/kg gemcitabine on days 10, 13, and 16 after tumor implantation. Starting after treatment with gemcitabine, animals developed a progressive cachexia and anorexia that could be attenuated by treatment with the anti-depressant mitrazepine [102]. Unfortunately, the authors failed to include an experimental cancer group without any treatment as a control to assess the true extent of gemcitabine on cachexia progression. In a bladder cancer model, chemotherapy with gemcitabine or the combination of cisplatin and gemcitabine resulted in cachexia, while untreated tumor-bearing animals remained weight stable [103]. Chemotherapy significantly up-regulated key catabolic proteins like myostatin, MuRF-1, MAFbx, as well as proteasome activity, down-regulated anabolic mediators like IGF-1 and increased inflammatory cytokines compared to the tumor alone [103,104]. Cisplatin also causes muscle atrophy in non-tumor-bearing mice that have been treated with 3 mg/kg/d cis-platin on 4 consecutive days, which was partially prevented by exercise [105]. A recent study comparing the effects of the colon-26 cancer cachexia model and the FOLFIRI regimen (5-fluorouracil, irinotecan, and leucovorin therapy showed that non-tumor-bearing animals receiving FOLFIRI had significantly lower body weight, gastrocnemius, tibialis and quadriceps weights, as well as reduced muscle fiber cross-sectional area leading to reduced muscle function [106]. Cancer-induced and chemotherapy-induced cachexia models also displayed distinct changes in flux through the tricarboxylic acid cycle and β-oxidation pathways [106]. Doxorubicin is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Treating mice with doxorubicin with a cumulative dose of 24 mg/kg during 2 weeks induced a loss of 10% skeletal and cardiac muscle mass, which was attenuated by pre-treatment with soluble activin receptor type IIB-FC (ACVR2B-Fc) [107].