Clinical & Experimental Metastasis最新文献

Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis.

Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2) has been related to transcriptional inhibition and chromatin compaction. Nevertheless, the biological functions and mechanisms of L3MBTL2 are undefined in breast cancer (BRCA). Here, we revealed that L3MBTL2 is responsible for the decline of Nischarin (NISCH), a well-known tumor suppressor, in BRCA, and explored the detailed mechanism. Knockdown of L3MBTL2 reduced monoubiquitination of histone H2A at lysine-119 (H2AK119ub), leading to reduced binding to the NISCH promoter and increased expression of NISCH. Meanwhile, the knockdown of L3MBTL2 decreased proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of BRCA cells, and increased apoptosis, which were abated by NISCH knockdown. Nucleolar transcription factor 1 (UBTF) induced the transcription of L3MBTL2 in BRCA, and the suppressing effects of UBTF silencing on EMT in BRCA cells were also reversed by NISCH knockdown. Knockdown of UBTF slowed tumor progression and attenuated lung tumor infiltration, whereas simultaneous knockdown of NISCH accelerated EMT and increased tumor lung metastasis. Taken together, our results show that L3MBTL2, transcriptionally activated by UBTF, exerts oncogenic functions in BRCA, by catalyzing H2AK119Ub and reducing expression of NISCH.

As a major energy source for cells, mitochondria are involved in cell growth and proliferation, as well as migration, cell fate decisions, and many other aspects of cellular function. Once thought to be irreparably defective, mitochondrial function in cancer cells has found renewed interest, from suggested potential clinical biomarkers to mitochondria-targeting therapies. Here, we will focus on the effect of mitochondria movement on breast cancer progression. Mitochondria move both within the cell, such as to localize to areas of high energetic need, and between cells, where cells within the stroma have been shown to donate their mitochondria to breast cancer cells via multiple methods including tunneling nanotubes. The donation of mitochondria has been seen to increase the aggressiveness and chemoresistance of breast cancer cells, which has increased recent efforts to uncover the mechanisms of mitochondrial transfer. As metabolism and energetics are gaining attention as clinical targets, a better understanding of mitochondrial function and implications in cancer are required for developing effective, targeted therapeutics for cancer patients.

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy.

In recent decades, the field of systemic cancer treatment has seen remarkable changes due to advancements in the understanding of cancer's biology, immunology, and genetic makeup. As a result, individuals with late-stage cancers are now achieving survival rates that were previously unattainable. The goal of personalized cancer therapy is to enhance clinical outcomes by customizing drug treatments to suit the unique genetic and/or epigenetic profiles of each patient's tumor. This approach aims to reduce the side effects commonly associated with ineffective treatments. Advances in genetic sequencing and molecular cytogenetics have been instrumental in identifying cancer-driving mutations and epigenetic irregularities, leading to the development of specific molecular therapies. This review article highlights the progress and success of targeted molecular therapies in treating malignant melanoma, illustrating the concept of personalized cancer treatment.

Cancer cells within a population are heterogeneous due to genomic mutations or epigenetic changes. The immune response to cancer especially the T cell repertoire within the cancer microenvionment is important to the control and growth of cancer cells. When a cancer clone breaks through the surveillance of the immune system, it wins the battle to overcome the host's immune system. In this review, the complicated profile of the cancer microenvironment is emphasized. The molecular evidence of immune responses to cancer has been recently established. Based on these molecular mechanisms of immune interactions with cancer, clinical trials based on checkpoint inhibition therapy against CTLA-4 and/or PD-1 versus PD-L1 have been successful in the treatment of melanoma, lung cancer and other types of cancer. The diversity of the T cell repertoire is described and the tumor infiltrating lymphocytes within the cancer may be expanded ex vivo and infused back to the patient as a treatment modality for adoptive immunotherapy.

Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.

Chemotherapy remains the primary treatment for most metastatic cancers. However, the response to chemotherapy and targeted agents is often transient, and concurrent development of resistance is the primary impediment to effective cancer therapy. Strategies to overcome resistance to treatment have focused on cancer cell intrinsic factors and the tumor microenvironment (TME). Recent evidence indicates that systemic chemotherapy has a significant impact on the host that either facilitates tumor growth, allowing metastatic spread, or renders treatment ineffective. These host responses include the release of bone marrow-derived cells, activation of stromal cells in the TME, and induction of different molecular effectors. Here, we provide an overview of chemotherapy-induced systemic host responses that support tumor aggressiveness and metastasis, and which contribute to therapy resistance. Studying host responses to chemotherapy provides a solid basis for the development of adjuvant strategies to improve treatment outcomes and delay resistance to chemotherapy. This review discusses the emerging field of host response to cancer therapy, and its preclinical and potential clinical implications, explaining how under certain circumstances, these host effects contribute to metastasis and resistance to chemotherapy.

Antigen-presenting cells (APCs) are pivotal mediators of immune responses. Their role has increasingly been spotlighted in the realm of cancer immunology, particularly as our understanding of immunotherapy continues to evolve and improve. There is growing evidence that these cells play a non-trivial role in cancer immunity and have roles dependent on surface markers, growth factors, transcription factors, and their surrounding environment. The main dendritic cell (DC) subsets found in cancer are conventional DCs (cDC1 and cDC2), monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), and mature and regulatory DCs (mregDC). The notable subsets of monocytes and macrophages include classical and non-classical monocytes, macrophages, which demonstrate a continuum from a pro-inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype, and tumor-associated macrophages (TAMs). Despite their classification in the same cell type, each subset may take on an immune-activating or immunosuppressive phenotype, shaped by factors in the tumor microenvironment (TME). In this review, we introduce the role of DCs, monocytes, and macrophages and recent studies investigating them in the cancer immunity context. Additionally, we review how certain characteristics such as abundance, surface markers, and indirect or direct signaling pathways of DCs and macrophages may influence tumor response to immune checkpoint blockade (ICB) therapy. We also highlight existing knowledge gaps regarding the precise contributions of different myeloid cell subsets in influencing the response to ICB therapy. These findings provide a summary of our current understanding of myeloid cells in mediating cancer immunity and ICB and offer insight into alternative or combination therapies that may enhance the success of ICB in cancers.