Do all roads lead to Rome? Routes to metastasis development

Abstract

Metastasis, the life-threatening aspect of cancer, is a systemic disease process. Considerable progress has been made in recent years regarding how tumor cells circulating in the blood and lymphatic systems interact with and extravasate into secondary sites, and what determines whether these disseminated tumors cells survive, remain dormant or go on to form macrometastases. New insights into the routes that tumor cells take once leaving the primary tumor have emerged. Novel concepts regarding early seeding of metastases coupled to parallel progression, self-seeding of primary tumors by circulating tumor cells and the induction of premetastatic niches in distant organs by primary tumors have come to the fore. The perceived role of the lymphatic system in determining patterns of metastasis formation in distant organs has been reassessed. Together these new insights have the potential to offer new therapeutic options. In particular, the regulation of tumor cell dormancy emerges as a key event in metastasis formation, and therapeutic control of dormancy holds the promise of rendering cancer a chronic rather than life-threatening disease.Cancer patient prognosis is determined in the main by the emergence of metastases from disseminated tumor cells (DTCs) that lodge and grow out as secondary tumors in distant organs. For most tumor types the diagnosis of metastatic cancer is regarded as terminal, and the effects of metastatic growth, for example impairment of vital organ function and increasing tumor burden to lethal levels are thought to be responsible for more than 90% of deaths of cancer patients. [1][2][3] While metastasis by direct extension into body cavities is a feature of some types of cancer, 4 most metastases develop from tumor cells disseminated through the circulatory system. Although metastasis is a systemic disease process, the majority of research efforts in this area since the advent of the molecular era have focused on understanding the process of local invasion. Changes in cell adhesion, activation of proteolysis and the acquisition of motile properties by tumor cells are now well accepted as key events in local invasion and entry into the vascular system. 4,5 The activation of endogenous morphogenetic programmes such as EMT is also thought to play a role. 6 Intravital imaging has proffered an unparalleled glimpse into how tumor cells invade through tissues and enter capillaries. [7][8][9][10]

Metastatic Tumors to the Jaws and Mouth

“…Cancer cells reinitiate their proliferative programs at the target sites, thereby generating macroscopic, clinically detectable neoplastic growths referred to as 'metastatic colonization' [1][2][3]. Metastasis is a highly inefficient process, in which only a small minority out of thousands of cells released into the circulation each day eventually succeeds in constituting an overt colony at a distant organ [11][12][13][14].…”

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

“…Tumor metastasis is a highly complex molecular and cellular process (reviewed in Sleeman et al (2011)). Local invasion of tumor cells involves changes in adhesive properties, activation of proteolysis and acquisition of cell motility.…”

Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells

“…Migration was assessed using a wound-healing assay. The cells were seeded at 2x10 4 MDA-MB-231 and MCF-7 cells per well and cultured for 24 h. After scraping the cell monolayer with a sterile micropipette tip (Axygen, Union City, CA, USA), the wells were washed with PBS, and treated with LPS (5 µg/ml) or co-treated with LPS (5 µg/ml) and SK (5 µM). The first image of each scratch was obtained at time zero.…”

“…The prognosis of patients with advanced cancer is associated with the degree of aggressive metastasis (4,5). Thus, elucidation of the mechanisms involved in the metastasis of cancer is imperative as there are limited effective therapies once the cancer has spread.…”