Cancer and Metastasis Reviews

Adipocytokines and disease progression in endometrial cancer: a systematic review

AbstractThe objective of the study was to document the effect of adipocytokines on endometrial cancer progression. A search of the databases CINAHL, Medline, PubMed, Cochrane, Web of Science, Embase and Google Scholar was performed for English language articles from January 2000 to December 2020 using the keywords: (Endometrial cancer) AND (progression OR metastasis) AND (adipocytokine OR adiponectin OR leptin OR visfatin OR IL-6 OR TNF-α OR adipokine OR cytokine). Forty-nine studies on adipocytokines have been included in this review. Adiponectin has been linked with anti-proliferative and anti-metastatic effects on endometrial cancer cells and is associated with a better prognosis. Leptin, visfatin and resistin are linked to the stimulation of endometrial cancer growth, proliferation, invasion and metastasis and are associated with worse prognosis or with a higher grade/stage of endometrial cancer. IL-6, Il-11, IL-31, IL-33, TNF-α, TGF-β1, SDF-1 and CXCR are involved in endometrial cancer cell growth and metastasis or involved in epithelial mesenchymal transformation (EMT) or associated with advanced disease. Adipocytokines have been found to directly impact endometrial cancer cell proliferation, invasion and migration. These molecules and their signalling pathways may be used to determine prognosis and course of the disease and may also be exploited as potential targets for cancer treatment and prevention of progression.

LGR5: An emerging therapeutic target for cancer metastasis and chemotherapy resistance

Abstract Cancer stem cells play an important role in tumor progression and chemotherapy resistance. Leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) has been identified as a cancer stem cell marker in several cancer types. LGR5 is involved in cancer development and progression via several pathways including WNT/β-catenin signaling pathway. LGR5 plays a role in tumor progression by promoting cancer cell migration, invasion, metastasis, and angiogenesis in many cancers including colorectal, brain, gastric, and ovarian cancer. This review summarises the current knowledge on the expression and functional role of LGR5 in cancers, the molecular mechanisms regulated by LGR5, and the relationship between LGR5 and chemotherapy resistance. The review also includes highlights potential strategies to inhibit LGR5 expression and function. The majority of functional studies have shown that LGR5 plays an important role in promoting cancer progression, metastasis and chemotherapy resistance however, in some contexts LGR5 can also activate tumor-suppressive pathways and LGR5 negative cells can also promote cancer progression. The review highlights that targeting LGR5 is a promising anti-cancer treatment but the functional effect of LGR5 on tumor cells is complex may be dependent on cancer type, tumor microenvironment and cross-talk with other molecules in the LGR5 signaling pathway.

The adipocyte microenvironment and cancer

Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.

Tumor-associated fibrosis: a unique mechanism promoting ovarian cancer metastasis and peritoneal dissemination

AbstractEpithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.

Ribosomal rodeo: wrangling translational machinery in gynecologic tumors

The role of caspase-8 in the tumor microenvironment of ovarian cancer

AbstractCaspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.

What recent primary studies tell us about ovarian teratomas in children: a scoping review

AbstractOur knowledge of ovarian teratomas in children is still far from complete, and much remains to be discovered. Here, we conduct a scoping review of the primary research related to ovarian teratomas in pediatric age. To our knowledge, there is no published synthesis of the literature surrounding ovarian teratomas in children using scoping review methodology. We identified 24 studies from 11 countries; 18 studies were retrospective, 3 were prospective, and 3 were experimental. There were 6 studies concerning mature teratomas, 5 concerning immature teratomas, and 13 that included both tumor types. Overall, 9 out of all the studies concerned more than 50 patients. We revealed 7 major branches of research within the topic of ovarian teratoma in pediatric population: recurrence rate/relapse and follow-up strategy, malignant potential, prognostic factors, use of sparing surgery, differences between the use of laparoscopy and laparotomy, use of chemotherapy, and additional examinations to test the character of the lesion (immature vs. mature). This scoping review has revealed a number of knowledge gaps in the evidence base for pediatric ovarian teratomas. Overall, this topic has not been extensively explored, and more research dedicated exclusively to this tumor and patient population is required.

Hematological toxicity of parp inhibitors in solid tumors: a systematic review and safety meta-analysis

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are effective agents in different tumor types. A typical class of adverse events (AEs) associated with these agents, often leading to treatment modifications and discontinuations of treatment, is hematological toxicity. In our systematic review and safety meta-analysis, we investigated the incidence and risk of all grades and ≥ grade (G) 3 hematological AEs, including anemia, neutropenia, thrombocytopenia, and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) due to PARPis, used alone or in combination, in patients diagnosed with solid tumors. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases, the American Society of Clinical Oncology, and the European Society of Medical Oncology meeting abstracts for randomized clinical trials (RCTs) concerning the use of PARPis in patients with solid tumors. The search deadline was April 30, 2024. We calculated risk ratios (RRs) for all-grade and ≥ G3 AEs of PARPis versus non-PARPis. 31 phase II/III RCTs were included. Anemia was the most common all-grade (49.2%) and ≥ G3 AE (25.0%). The administration of PARPis significantly increased the risk of developing all grades of anemia (RR = 2.15, p < 0.00001), neutropenia (RR = 1.50, p = 0.0002), and thrombocytopenia (RR = 2.59, p < 0.00001) compared to non-PARPis. Similarly, a significant increase in the risk of ≥ G3 anemia (RR = 5.43, p < 0.00001), neutropenia (RR = 1.70, p = 0.002), and thrombocytopenia (RR = 5.42, p < 0.00001) was detected. PARPis did not increase the risk of AML/MDS (p = 0.86). PARPis increase the risk of hematologic toxicity compared to other treatments in solid tumors. Clinicians should be aware of this risk, especially given the expected increase in PARPis use in the next year in different tumor types.

Spatial omics: applications and utility in profiling the tumor microenvironment