bims-myxlip 2021-04-04 papers

Issue of 2021–04–04
three papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2021 Mar 03. pii: 1086. [Epub ahead of print]13(5):

Role of Tumor-Associated Macrophages in Sarcomas.

Tomohiro Fujiwara, John Healey, Koichi Ogura, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Miho Kure, Hiroshi Tazawa, Eiji Nakata, Toshiyuki Kunisada, Toshiyoshi Fujiwara, Toshifumi Ozaki.

Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

Keywords: clinical trial; immunotherapy; prognosis; sarcoma; tumor-associated macrophage

DOI: https://doi.org/10.3390/cancers13051086

Jpn J Clin Oncol. 2021 Mar 29. pii: hyab033. [Epub ahead of print]

Prognostic factors and impact of surgery in patients with metastatic soft tissue sarcoma at diagnosis: A population-based cohort study.

Liuzhe Zhang, Toru Akiyama, Takashi Fukushima, Shintaro Iwata, Yusuke Tsuda, Katsushi Takeshita, Akira Kawai, Sakae Tanaka, Hiroshi Kobayashi.

BACKGROUND: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear.
METHODS: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors.
RESULTS: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival.
CONCLUSIONS: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery.

Keywords: metastasis; overall survival; prognostic factor; soft tissue sarcoma; surgery

DOI: https://doi.org/10.1093/jjco/hyab033

Int J Mol Sci. 2021 Mar 09. pii: 2778. [Epub ahead of print]22(5):

Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis.

Mariam Markouli, Dimitrios Strepkos, Efthimia K Basdra, Athanasios G Papavassiliou, Christina Piperi.

Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate in the widespread changes of gene expression that characterize the metastatic phenotype. At the chromatin level, active and repressive histone post-translational modifications (PTM) in association with pleiotropic transcription factors regulate pivotal genes involved in the initiation of the EMT process as well as in intravasation and anoikis resistance, playing a central role in the progression of tumors. Herein, we discuss the main epigenetic mechanisms associated with the different steps of metastatic process, focusing in particular on the prominent role of histone modifications and the modifying enzymes that mediate transcriptional regulation of genes associated with tumor progression. We further discuss the development of novel treatment strategies targeting the reversibility of histone modifications and highlight their importance in the future of cancer therapy.

Keywords: EMT; acetylation; anoikis resistance; drug targeting; epigenetics; histone modifications; intravasation; metastasis; methylation; novel therapies

DOI: https://doi.org/10.3390/ijms22052778