Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer

Abstract

Lymphovascular invasion (LVI), the presence of malignant cells within lymphovascular channels, is a crucial step in the invasion-metastasis cascade. LVI, when identified morphologically in the peritumoural area, is regarded as an indicator of metastatic potential and is strongly associated with a poor prognosis in many solid tumours, including breast cancer (BC). Although molecular mechanisms associated with the development of LVI have been extensively studied, details of driver genes, and molecular pathways and mechanisms involved in its development in BC, remain poorly defined. Although invasive BC cells have the ability to invade surrounding stroma, only those that can interact with endothelial cells, penetrate the vascular wall and withstand the intravascular stress will develop LVI and complete metastatic dissemination. Identification of additional molecular events associated with LVI in the primary tumour and characterisation of the contribution of the tumour micro-environment to modulating biological processes leading to LVI in BC remain a challenging task. This stems not only from the complexity of the molecular alterations in the primary tumour and the interactions with different components of its micro-environment but also from the subjective nature of LVI assessment in human BC. In this review, we discuss the clinicopathological features and the current knowledge of the molecular mechanisms underlying LVI in BC.

Genome profiles of lymphovascular breast cancer cells reveal multiple clonally differentiated outcomes with multi-regional LCM and G&T-seq

“…Tumor metastasis is a highly complex process that occurs through several steps, including tumor cell invasion of local tissue, intravasation and survival of tumor cells in the circulation, arrest and extravasation at a distant organ, micrometastasis formation, and finally metastatic colonization (Valastyan and Weinberg, 2011). Cancer cells can enter the circulation either directly by invading tumor associated blood vessels (termed blood vessel invasion or BVI), or indirectly by first traversing the lymphatic system in a process known as lymphovascular invasion (LVI) (Aleskandarany et al, 2015, Rakha et al, 2018, Nathanson et al, 2015. In breast cancer, the majority of vessel intravasion takes place at the primary tumor location via LVI and the lymphatic network serves as a conduit for the metastatic spread of this disease (Rakha et al, 2011, Aleskandarany et al, 2015, Mohammed et al, 2007.…”

“…Cancer cells can enter the circulation either directly by invading tumor associated blood vessels (termed blood vessel invasion or BVI), or indirectly by first traversing the lymphatic system in a process known as lymphovascular invasion (LVI) (Aleskandarany et al, 2015, Rakha et al, 2018, Nathanson et al, 2015. In breast cancer, the majority of vessel intravasion takes place at the primary tumor location via LVI and the lymphatic network serves as a conduit for the metastatic spread of this disease (Rakha et al, 2011, Aleskandarany et al, 2015, Mohammed et al, 2007. Once within the lymphatic vasculature, breast cancer cells are diverted, along with immune cells and lymphatic fluid, to the local regional axillary lymph nodes where their outcome can vary from indefinite lymph node arrest, to entry into the circulation and subsequent formation of distant metastatic lesions (Nathanson et al, 2015).…”

“…Once within the lymphatic vasculature, breast cancer cells are diverted, along with immune cells and lymphatic fluid, to the local regional axillary lymph nodes where their outcome can vary from indefinite lymph node arrest, to entry into the circulation and subsequent formation of distant metastatic lesions (Nathanson et al, 2015). The rate at which cancer cells enter the lymphatic system and transit to the lymph nodes is influenced by a number of factors, including biomechanical forces from within the primary tumor and the lymphatic vessels, and the presence of chemokines and other immune elements that alter the primary tumor and lymphatic microenvironment (Aleskandarany et al, 2015, Nathanson et al, 2015, Ji, 2016, Lund et al, 2016, Pereira et al, 2015. Because the majority of breast cancer deaths result from metastatic spread (Howlader N, 2019), isolating and characterizing metastatic invasive cancer cells is often pursued as way to identify new medicinal targets to prevent or impede metastasis in breast cancer patients.…”

Saccharomyces cerevisiae-like 1 (SEC14L1) is a prognostic factor in breast cancer associated with lymphovascular invasion

“…Lymphovascular invasion is an independent prognostic parameter of poor outcome in invasive breast cancer and is major prerequisite for the development of metastasis [1][2][3]. Comprehension of the molecular mechanisms underlying lymphovascular invasion in breast cancer and unveiling its key-players could lead to unique therapeutic targets and improve risk prediction [4][5][6]. However, the sophistication of the molecular mechanisms underlying lymphovascular invasion as part of the invasion-metastasis cascade with involvement of several genes, diverse signaling pathways and interactions of tumor microenvironment in addition to the subjectivity of lymphovascular invasion morphological assessment in clinical samples renders this task highly challenging [6].…”

Coronin 1c and F-actin Promote Metastasis of Breast Cancer

“…Studies [3,4] have shown that metastasis of cancer cells to lymph nodes, distal tissues, or organs is one of the major causes of death in breast cancer patients. The survival rate of breast cancer patients with metastasis of cancer cells is also significantly reduced [5]. Therefore, studying the specific molecular mechanisms of breast cancer cell metastasis is of great importance to improve the clinical treatment and prolong the survival of patients with breast cancer.…”