Mechanisms of metastasis

Abstract

Metastasis is an enormously complex process that remains to be a major problem in the management of cancer. The fact that cancer patients might develop metastasis after years or even decades from diagnosis of the primary tumor makes the metastatic process even more complex. Over the years many hypotheses were developed to try to explain the inefficiency of the metastatic process, but none of these theories completely explains the current biological and clinical observations. In this review we summarize some of the proposed models that were developed in attempt to understand the mechanisms of tumor dissemination and colonization as well as metastatic progression.Metastasis is an extraordinarily complex process. To successfully colonize a secondary site a cancer cell must complete a sequential series of steps before it becomes a clinically detectable lesion. These steps typically include separation from the primary tumor, invasion through surrounding tissues and basement membranes, entry and survival in the circulation, lymphatics or peritoneal space and arrest in a distant target organ. These are usually, but not always [1], followed by extravasation into the surrounding tissue, survival in the foreign microenvironment, proliferation, and induction of angiogenesis, all the while evading apoptotic death or immunological response (Figure 1Metastasis is of great importance to the clinical management of cancer since the majority of cancer mortality is associated with disseminated disease rather than the primary tumor [2]. In most cases cancer patients with localized tumors have significantly better prognoses than those with disseminated tumors. Recent evidence suggests that the first stages of metastasis can be an early event [3] and that 60% to 70% of patients have initiated the metastatic process by the time of diagnosis. Therefore, an improved understanding of the factors leading to tumor dissemination is of vital importance. However, even patients that have no evidence of tumor dissemination at presentation are at risk for metastatic disease. Approximately one-third of women who are sentinel lymph node negative at the time of surgical resection of the primary breast tumor will subsequently develop clinically detectable secondary tumors [4]. Even patients with small primary tumors and node negative status (T1N0) at surgery have a significant (15% to 25%) chance of developing distant metastases [5].In spite of the prevalence of secondary tumors in cancer patients, metastasis is an extremely inefficient process. To successfully colonize a distant site, a cancer cell must complete all of the steps of the cascade. Failure to complete any one step results in failure to colonize and proliferate in the distant organ. As a result, tumors can shed millions of cells into the bloodstream daily [6], yet very few clinically relevant metastases are formed [7]. Although many steps in the metastatic process are thought to contribute to metastatic inefficiency, our incomplete understanding of this process suggests that we ...

Minimization of thermodynamic costs in cancer cell invasion

“…Metastatic tumor cells that leave the primary tumor have to break through the stromal tissue barrier, evade the immune system, and coordinate with other local cells during angiogenesis to finally set up a viable remote tumor. It has been estimated that less than 1% of the primary tumor cells are able to finish the metastasis cycle (2), and yet they contribute to more than 90% of the cancer-related deaths (3). Although the molecular details are still unclear, it is significant that the malignant transition is accompanied by a change in the metabolism pathway from the mitochondrial oxidation of pyruvate in mitochondria (an aerobic process) to the far less energy-efficient and ancient anaerobic pathway of glycolysis followed by lactic acid fermentation in the cytosol (4), known as the Warburg cycle (5).…”

MiR-129-5p is down-regulated and involved in migration and invasion of gastric cancer cells by targeting interleukin-8

“…An emerging body of evidence has suggests that the metastasis can be an early event [25]. It has been estimated that approximately 60% to 70% of patients show the metastatic involvement by the time of diagnosis [24]. Therefore, it is imperative to understand the factors that are responsible for tumor dissemination.…”

“…The capability of cell migration and invasion is regarded as one of the most critical determinant in the process of cancer metastasis, leading to morbidity and mortality. The development of metastasis is an extraordinarily complex and multi-step process that involves in complicated mechanisms [23,24]. An emerging body of evidence has suggests that the metastasis can be an early event [25].…”

MicroRNA-182 suppresses clear cell renal cell carcinoma migration and invasion by targeting IGF1R

“…The development of metastasis is a multistage process that is involved in many factors such as lymphangiogenesis, angiogenesis, and invasiveness of cancer cells [23,24]. It has been reported that metastases were present in up to 60-70% of patients by the time of diagnosis [24]. In addition, metastasis can be an early event feature and stay unnoticed until the diagnosis because of the asymptomatic status in the early stage [25,26].…”

“…Migration and invasion have been considered to be one of the most important determinants in the development and progression of tumor metastasis, which contribute to the leading causes of morbidity and mortality. The development of metastasis is a multistage process that is involved in many factors such as lymphangiogenesis, angiogenesis, and invasiveness of cancer cells [23,24]. It has been reported that metastases were present in up to 60-70% of patients by the time of diagnosis [24].…”