Clinical & Experimental Metastasis最新文献

This paper is a cross fertilization of ideas about the importance of molecular aspects of breast cancer metastasis by basic scientists, a pathologist, and clinical oncologists at the Henry Ford Health symposium. We address four major topics: (i) the complex roles of lymphatic endothelial cells and the molecules that stimulate them to enhance lymph node and systemic metastasis and influence the anti-tumor immunity that might inhibit metastasis; (ii) the interaction of molecules and cells when breast cancer spreads to bone, and how bone metastases may themselves spread to internal viscera; (iii) how molecular expression and morphologic subtypes of breast cancer assist clinicians in determining which patients to treat with more or less aggressive therapies; (iv) how the outcomes of patients with oligometastases in breast cancer are different from those with multiple metastases and how that could justify the aggressive treatment of these patients with the hope of cure.

Donald L. Morton, MD, epitomized one of America's dream scenarios: a person evolving from the humblest of origins to become an international celebrity in his profession, leading the world in the discipline of surgical oncology. His pioneering accomplishments in various roles have been well documented. Scientists, clinicians, students, and patients benefited from his contributions to the management of malignant diseases, particularly melanoma. His many attributes in pursuing the goal to cure malignant diseases are well known. Browsing the scientific literature reveals an almost unmatched publication record and continuous National Institutes of Health funding. He revealed dozens of original concealed ideas, not least of which is the tumor-draining regional lymph node, now called the sentinel lymph node (SLN). When others gave up on the original promise of immunotherapy, he saw the future, the clinical promise which has lately materialized in the control of previously untreatable malignancies. He regarded the fellowship-training of more than 100 surgical oncologists as one of his biggest achievements. In this article, we celebrate the human side of a man with creative courage and far-reaching insight.

Lymphedema and specifically cancer-related lymphedema is not the main focus for both patients and physicians dealing with cancer. Its etiology is an unfortunate complication of cancer treatment. Although lymphedema treatments have gained an appreciable consensus, many practitioners have developed and prefer their own specific protocols and this is especially true for conventional (manual) versus surgical treatments. This collection of presentations explores the incidence and genetics of cancer-related lymphedema, early detection and monitoring techniques, both conventional and operative treatment options, and the importance and role of exercise for patients with cancer-related lymphedema. These assembled presentations provide valuable insights into the challenges and opportunities presented by cancer-related lymphedema including the latest research, treatments, and exercises available to improve patient outcomes and quality of life.

Most cancers and in particular carcinomas metastasise via the lymphatics to draining lymph nodes from where they can potentially achieve systemic dissemination by invasion of high endothelial blood venules (HEVs) in the paracortex [1, 2]. Currently however, the mechanisms by which tumours invade and migrate within the lymphatics are incompletely understood, although it seems likely they exploit at least some of the normal physiological mechanisms used by immune cells to access lymphatic capillaries and traffic to draining lymph nodes in the course of immune surveillance, immune modulation and the resolution of inflammation [3, 4]. Typically these include directional guidance via chemotaxis, haptotaxis and durotaxis, adhesion to the vessel surface via receptors including integrins, and junctional re-modelling by MMPs (Matrix MetalloProteinases) and ADAMs (A Disintegrin And Metalloproteinases) [5-7]. This short review focusses on a newly emerging mechanism for lymphatic entry that involves the large polysaccharide hyaluronan (HA) and its key lymphatic and immune cell receptors respectively LYVE-1 (Lymphatic Vessel Endothelial receptor) and CD44, and outlines recent work which indicates this axis may also be used by some tumours to aid nodal metastasis.

In-transit metastasis (ITM) develop in approximately 1 in 10 patients with melanoma and the disease course can vary widely. Surgical resection is the gold-standard treatment; however, ITM are often surgically unresectable due to size, distribution, and/or anatomic involvement. Oncolytic viral therapies are one category of non-surgical treatment options available for ITM. They induce tumor cell lysis and systemic anti-tumor activity through selective infection of tumor cells by naturally occurring or genetically modified factors. While there are numerous oncolytic viral therapies in various stages of development for the treatment of ITM, this discussion focuses on the mechanism and available literature for the two most established herpes virus-based therapies.

The molecular mechanisms underlying sensitivity and resistance to radiotherapy is an area of active investigation and discovery as its clinical applications have the potential to improve cancer patients' outcomes. In addition to the traditional pathways of radiation biology, our knowledge now includes molecular pathways of radiation sensitivity and resistance which have provided insights into potential targets for enhancing radiotherapy efficacy. Sensitivity to radiotherapy is influenced by the intricate interplay of various molecular mechanisms involved in DNA damage repair, apoptosis, cellular senescence, and epigenetics. Translationally, there have been several successful applications of this new knowledge into the clinic, such as biomarkers for improved response to chemo-radiation. New therapies to modify radiation response, such as the poly (ADP-ribose) polymerase (PARP) inhibitors, derived from research on DNA repair pathways leading to radiotherapy resistance, are being used clinically. In addition, p53-mediated pathways are critical for DNA damage related apoptosis, cellular senescence, and cell cycle arrest. As the understanding of genetic markers, molecular profiling, molecular imaging, and functional assays improve, these advances once translated clinically, will help propel modern radiation therapy towards more precise and individualized practices.

The concept of liquid biopsy analysis has been established more than a decade ago. Since the establishment of the term, tremendous advances have been achieved and plenty of methods as well as analytes have been investigated in basic research as well in clinical trials. Liquid biopsy refers to a body fluid-based biopsy that is minimal-invasive, and most importantly, allows dense monitoring of tumor responses by sequential blood sampling. Blood is the most important analyte for liquid biopsy analyses, providing an easily accessible source for a plethora of cells, cell-derived products, free nucleic acids, proteins as well as vesicles. More than 12,000 publications are listed in PubMed as of today including the term liquid biopsy. In this manuscript, we critically review the current implications of liquid biopsy, with special focus on circulating tumor cells, and describe the hurdles that need to be addressed before liquid biopsy can be implemented in clinical standard of care guidelines.

Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial-mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.