MG-132 br Experimental Cell Research br journal homepage www elsevier com
Experimental Cell Research
journal homepage: www.elsevier.com/locate/yexcr
Circulation patterns and seed-soil compatibility factors cooperate to cause T cancer organ-specific metastasis
Yusheng Lua,b, Shu Lianb, Yunlong Chengb, Yuying Yec, Xiaodong Xieb, Chengbin Fud, Chen Zhanga, Yewei Zhub , M. Iqbal Parkere , Lee Jiaa,b, a Institute of Oceanography, Minjiang University, Fuzhou 350108, China b Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350116, China c Department of Otolaryngology, Fujian Provincial People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China d Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China e Division of Medical Biochemistry and Institute for infectious disease and molecular Medicine, University of Cape Town, Observatory 7925, South Africa
Cancer metastasis dynamics Circulating tumor cells Organ-specific cancer metastasis Circulation patterns Bloodstream microenvironment ‘seed–soil’ compatibility factors
Despite the recognition of the lethality of cancer metastasis and the importance of developing specific anti-metastasis therapies directed at the cancer metastatic cascade, the dynamics of cancer metastasis remains poorly understood. In this study, we examined the dynamics of circulating tumor cell (CTC) survival in the bloodstream using experimental mouse models. CTCs were arrested in the MG-132 by adhesion to vascular endothelium within a few minutes after injection into the bloodstream. The loss of CTCs from the circulation followed a bi-phasic decay pattern, with the number of CTCs in the bloodstream being closely associated with the number of blood circulation cycles. The calculated in vivo Vd (apparent volume of distribution) of the CTC revealed organ specific binding of the CTCs. Moreover, confocal microscopy, in vivo fluorescence imaging in syngeneic mouse metastatic models and analysis of blood circulation patterns support the notion of organ-specific tumor me-tastasis. The present study suggests that organ-specific tumor metastasis is influenced by cooperation between blood circulation patterns and ‘seed-soil’ compatibility factors. These new findings provide further insights for optimized cancer metastatic prevention strategies such as by creating a hostile circulation microenvironment and targeting the organ-specific ‘seed–soil’ compatibility factors.
The ability to metastasize is a hallmark of malignant tumors, with metastasis being the cause of about 90% of cancer-associated deaths [1,2]. Metastasis is the main threat to cancer survivors, of whom 30–70% will eventually develop metastases within 2–5 years after surgery, chemotherapy or radiotherapy [3,4]. In the United States alone, nearly 14.5 million cancer survivors were alive in 2014 and the estimated number of cancer survivors are expected increase to 19 million by 2024 . Although many anti-metastasis therapies have been developed over the last few years, the curative effect of most cancer survivors remains unsatisfactory. This challenge therefore un-derlines the importance of a better understanding of the metastatic process to develop specific therapies to prevent metastasis after surgical removal of primary tumor.
Distant metastases rely on dissemination of circulating tumor cells (CTCs) via the blood and lymphatic circulation, a highly complex process whereby cancer cells must be successfully complete a series of critical steps. These include shedding of cells from a primary tumor into the circulation, survival of the CTCs in the blood/lymphatic system, initial arrest in a new organ, extravasation into the tissue parenchyma, survival and maintenance of growth and subsequent vascularization of the metastasized tumor [6,7]. Even though large primary tumors can shed millions of cancer cells into the blood circulation system every day, very few cells succeed at reestablishing metastases in distant or-gans [6,7]. Although metastasis is a very inefficient process, many challenges exist in targeting the cancer metastatic cascade and there is currently no effective therapy to target this process. A primary reason is that current targeted therapies are directed against the later stages in metastasis when the cancer cells have already seeded in various