Is There One Key Step in the Metastatic Cascade?

Abstract

The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs).

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis—Results from the Adjuvant SUCCESS A Trial

“…Furthermore, it could be shown that the presence of CTCs during follow-up, two years after the completion of primary breast cancer treatment, was associated with reduced disease-free and overall survival, especially in patients who demonstrated positive CTC status both before treatment and during follow-up [ 12 ]. These results are in line with the concept of the metastatic cascade, which postulates that tumor dormancy, epithelial-to-mesenchymal plasticity, or stemness protect minimal distant residual disease from systemic treatment [ 4 , 5 , 7 , 38 ].…”

“…In the first step, single tumor cells invade the surrounding tissue and then enter the circulatory and lymphatic system. Therefore, these shedding cells have to escape the immune system and survive surrounded by mesenchymal environment [ 4 ].…”

Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence

“…Metastatic spread of cancer is a complex, poorly understood process, and involves multiple steps, such as angiogenesis acquisition of invasive properties through epigenetic and genetic alterations, intravasation through the basement membrane, extravasation of some cancer cells to distal tissues, and tumor-stroma interactions ( Nguyen and Massagué, 2007 ; Fatima et al, 2018 ). Metastatic cells outgrowth in a foreign tissue environment is considered as the rate-limiting step of breast cancer metastasis and in this stage, breast cancer cells are difficult to detect and show resistance to chemotherapy due to lack of proliferation ( Giancotti, 2013 ; Dujon et al, 2021 ). To date, this remains a clinical obstacle, since the patients considered as “survivors” can develop metastatic tumors years later.…”

Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anticancer and antimetastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

“…To the best of our knowledge, nine isozymes out of eleven metal-dependent HDACs have been linked to the metastatic events in breast cancer (Supplementary Table S1). Metastasis, the capacity of malignant cells to colonize from primary tumors to distant organs, remains a significant consequence of cancer morbidity and mortality; therefore, ways to prevent the activation of metastasis events may highly benefit cancer patient [32,33] . Among the events that comprise the metastatic cascade, one of the first steps is the acquisition of motility and migratory abilities of transformed cells that are essential for their capacity to mobilize and access to the circulation, gaining options to arrive at distant tissues and organs [33] .…”

“…Metastasis, the capacity of malignant cells to colonize from primary tumors to distant organs, remains a significant consequence of cancer morbidity and mortality; therefore, ways to prevent the activation of metastasis events may highly benefit cancer patient [32,33] . Among the events that comprise the metastatic cascade, one of the first steps is the acquisition of motility and migratory abilities of transformed cells that are essential for their capacity to mobilize and access to the circulation, gaining options to arrive at distant tissues and organs [33] . To determine the capacity of the developed HDACi to influence cancer cell motility, we selected the highly metastatic cell line MDA-MB-231; these cells represent triple-negative breast cancer (TNBC), which are poorly responsive to hormonal therapies and associated with worse prognosis of breast cancer patients.…”