Clinical & Experimental Metastasis最新文献

The standard of care for patients with resectable stage III/IV melanoma classically included upfront resection with adjuvant therapy. However, in more recent years, the amount of systemic therapies available for neoadjuvant use for these patients has increased. This article reviewed clinical trials investigating neoadjuvant therapy for patients with resectable stage III/IV melanoma. The outcomes of these trials have identified optimal treatment regimens to maximise patient response and minimize toxicities. Additionally, the date demonstrate advantages to neoadjuvant treatment compared to adjuvant therapy alone. Further research is needed to utilize a patient's response to neoadjuvant treatment for prognostication and creation of an individualized treatment plan.

Lymphatic metastasis is the dominant route of initial spread for most solid tumors. For many such malignancies, including melanomas, surgical treatment previously included removal of all potentially draining regional lymph nodes (elective node dissection). The advent of lymphatic mapping and sentinel lymph node (SLN) biopsy allowed accurate pathologic assessment of the metastatic status of regional nodes and spared patients full dissection if their SLN was clear. In melanoma, recent clinical research has demonstrated that complete lymph node dissection is not clinically beneficial, even for patients with sentinel node metastases and that patients with high-risk primary melanomas benefit from adjuvant systemic immunotherapy, even without nodal disease. These two changes in the standard of care have led to some interest in abandoning surgical nodal staging via the sentinel lymph node biopsy procedure. However, this appears to be premature and potentially detrimental to optimal patient management. The ongoing value of sentinel node biopsy stems from its ability to provide critically important prognostic information as well as durable regional nodal disease control for most patients with nodal metastases, even in the absence of complete dissection of the basin. It also provides an opportunity to identify novel prognostic and predictive immunologic and molecular biomarkers. While it is certainly possible that additional changes in melanoma therapy will make sentinel lymph node biopsy obsolete in the future, at present it remains a minimally invasive, low morbidity means of improving both staging and outcomes.

Cancer-related fatigue, pain, gastrointestinal and other symptoms are among the most familiar complaints in practically every type and stage of cancer, especially metastatic cancers. Such symptoms are also related to cancer oxidative stress and the damage instigated by cancer cytotoxic therapies to cellular membranes, especially mitochondrial membranes. Cancer cytotoxic therapies (chemotherapy and radiotherapy) often cause adverse symptoms and induce patients to terminate their anti-neoplastic regimens. Cancer-related fatigue, pain and other symptoms and the adverse effects of cancer cytotoxic therapies can be safely moderated with oral Membrane Lipid Replacement (MLR) glycerolphospholipids and mitochondrial cofactors, such as coenzyme Q₁₀. MLR provides essential membrane lipids and precursors to maintain mitochondrial and other cellular membrane functions and reduces fatigue, pain, gastrointestinal, inflammation and other symptoms. In addition, patients with a variety of chronic symptoms benefit from MLR supplements, and MLR also has the ability to enhance the bioavailability of nutrients and slowly remove toxic, hydrophobic molecules from cells and tissues.

High rates of mortality in non-small cell lung cancer lung cancer is due to inherent and acquired resistance to systemic therapies and subsequent metastatic burden. Metastasis is supported by suppression of the immune system at secondary organs and within the circulation. Modulation of the immune system is now being exploited as a therapeutic target with immune checkpoint inhibitors. The tracking of therapeutic efficacy in a real-time can be achieved with liquid biopsy, and evaluation of circulating tumour cells and the associated immune cells. A stable liquid biopsy biomarker for non-small cell lung cancer lung cancer has yet to be approved for clinical use. We performed a cross-sectional single-site study, and collected liquid biopsies from patients diagnosed with early, locally advanced, or metastatic lung cancer, undergoing surgery, or systemic therapy (chemotherapy/checkpoint inhibitors). Evaluation of overall circulating tumour cell counts, or cluster counts did not correlate with patient outcome. Interestingly, the numbers of Pan cytokeratin positive circulating tumour cells engulfed by tumour associated monocytes correlated strongly with patient outcome independent of circulating tumour cell counts and the use of checkpoint inhibitors. We suggest that Pan cytokeratin staining within monocytes is an important indicator of tumour-associated inflammation post-therapy and an effective biomarker with strong prognostic capability for patient outcome.

Glycosylation changes of cancer cells are known to be associated with malignant progression and metastases and potentially determine the organ-selective nature of metastasis as theorized by Paget (Lancet 1:571-573, 1889). Cellular glycans play a variety of roles in the processes of metastasis and may be unique to the cells that metastasize to different organs. We analyzed the glycosylation profiles of the primary tumor and tumors metastasized to lymph node, liver, lung, brain, bone, thyroid, kidney, adrenal, small intestine and pancreas in an autopsy case of breast cancer employing a lectin microarray with 45 lectins. Clustering analysis of the data revealed that metastatic breast cancer cells were categorized into several clusters according to their glycosylation profiles. Our results provide a biological basis to understand differential phenotypes of metastatic breast cancer cells potentially reflecting clonal origin, which does not directly reflect genomic or genetic changes or microenvironmental effects but connects to glycosylation profiles.

Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases. The mechanistic explanations behind these findings remain poorly understood. We recently reported that young mice, in comparison to older mice, developed significantly greater brain metastases in four mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins potentially contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse hematogenous model of brain-tropic triple-negative breast cancer (MDA-MB-231BR), we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins potentially contributing to age-dependent rates of brain metastasis. Pathway analysis revealed significant alterations in signaling pathways, particularly in the metastatic microenvironment, modulating tumorigenesis, metabolic processes, inflammation, and neuronal signaling. Tenascin C (TNC) was significantly elevated in all laser microdissection (LMD) enriched compartments harvested from young mice relative to older hosts, which was validated and confirmed by immunoblot analysis of whole brain lysates. Additional in vitro studies including migration and wound-healing assays demonstrated TNC as a positive regulator of tumor cell migration. These results provide important new insights regarding microenvironmental factors, including TNC, as mechanisms contributing to the increased brain cancer metastatic phenotype observed in young breast cancer patients.

Brain metastasis, characterized by poor clinical outcomes, is a devastating disease. Despite significant mechanistic and therapeutic advances in recent years, pivotal improvements in clinical interventions have remained elusive. The heterogeneous nature of the primary tumor of origin, complications in drug delivery across the blood-brain barrier, and the distinct microenvironment collectively pose formidable clinical challenges in developing new treatments for patients with brain metastasis. Although current preclinical models have deepened our basic understanding of the disease, much of the existing research on brain metastasis has employed a reductionist approach. This approach, which often relies on either in vitro systems or in vivo injection models in young and treatment-naive mouse models, does not give sufficient consideration to the clinical context. Given the translational importance of brain metastasis research, we advocate for the design of preclinical experimental models that take into account these unique clinical challenges and align more closely with current clinical practices. We anticipate that aligning and simulating real-world patient conditions will facilitate the development of more translatable treatment regimens. This brief review outlines the most pressing clinical challenges, the current state of research in addressing them, and offers perspectives on innovative metastasis models and tools aimed at identifying novel strategies for more effective management of clinical brain metastasis.

Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of diseases including cancer. They play a complex role in cancers, having both tumour suppressor and promoter properties. In addition, a single miRNA can be involved in regulating several mRNAs or many miRNAs can regulate a single mRNA, therefore assessing these roles is essential to a better understanding in cancer initiation and development. Pancreatic cancer is a leading cause of cancer death worldwide, in part due to the lack of diagnostic tools and limited treatment options. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by major genetic mutations that drive cancer initiation and progression. The regulation or interaction of miRNAs with these cancer driving mutations suggests a strong link between the two. Understanding this link between miRNA and PDAC progression may give rise to novel treatments or diagnostic tools. This review summarises the role of miRNAs in PDAC, the downstream signalling pathways that they play a role in, how these are being used and studied as therapeutic targets as well as prognostic/diagnostic tools to improve the clinical outcome of PDAC.