Organotropism: new insights into molecular mechanisms of breast cancer metastasis

Abstract

Metastasis accounts for 90% of breast cancer mortality. Despite the significant progress made over the past decade in cancer medicine our understanding of metastasis remains limited, therefore preventing and targeting metastasis is not yet possible. Breast cancer cells preferentially metastasize to specific organs, known as "organotropic metastasis", which is regulated by subtypes of breast cancer, host organ microenvironment, and cancer cells-organ interactions. The cross-talk between cancer cells and host organs facilitates the formation of the premetastatic niche and is augmented by factors released from cancer cells prior to the cancer cells' arrival at the host organ. Moreover, host microenvironment and specific organ structure influence metastatic niche formation and interactions between cancer cells and local resident cells, regulating the survival of cancer cells and formation of metastatic lesions. Understanding the molecular mechanisms of organotropic metastasis is essential for biomarker-based prediction and prognosis, development of innovative therapeutic strategy, and eventual improvement of patient outcomes. In this review, we summarize the molecular mechanisms of breast cancer organotropic metastasis by focusing on tumor cell molecular alterations, stemness features, and cross-talk with the host environment. In addition, we also update some new progresses on our understanding about genetic and epigenetic alterations, exosomes, microRNAs, circulating tumor cells and immune response in breast cancer organotropic metastasis.

Fig. 1

Summary of breast cancer organotropic metastases. The site-specific organotropic metastasis is regulated by the breast cancer subtypes, different gene signatures and signaling pathways of metastatic tumor cells. Bone is the most common site of metastatic breast cancer patients, with the second most common site is brain, and liver and lungs are the next

Fig. 2

Vicious cycle of bone metastasis. Tumor-derived factors such as OPN, PTHrP, heparanase, IL-1, IL-6 and PGE2 enhance the osteoclasts formation and promote bone resorption.^, Resorbed bones release bone-derived growth factors, such as IGF1, PDGF, and TGFβ, and calcium, which in turn stimulate tumor growth. Tumor cells that reach in the bone microenvironment secrete PTHrP to initiate osteolysis and stimulate bone lining osteoblasts. In response, the expression of RANKL is upregulated by activated osteoblasts and binds to its receptor RANK to activate RANKL-RANK signaling pathway, and leading to bone resorption

Fig. 3

Brain metastatic cancer cells breach the blood–brain barrier (BBB). BBB is composed of capillary endothelial cells, basal lamina, pericytes and astrocytic end-feet. CD44, VEGF and CXCR4 can enhance the transendothelial migration of tumor cells by disrupting endothelial integrity. Ang-2 increases BBB permeability by impairing ZO-1 and Claudin-5 tight junction protein structures. COX2, HBEGF, and ST6GALNAC5 mediate cancer cell passage through the BBB^,

Fig. 4

Lung metastatic cancer cells overcome the inhibition of lung cell-derived BMPs. BMPs secreted by lung resident cells can inhibit tumor growth by turning tumor cells into a dormancy state. Cancer cell-derived Coco and GALNTs can inhibit BMPs and reactivates dormant cancer cells to outgrowth in the lung. GALNTs support metastasis outgrowth by inducing macrophage infiltration and exploiting macrophage-derived FGFs

Fig. 5

Dysregulation of cell adhesion molecules N-cadherin and E-cadherin in liver metastasis. N-cadherin promotes motility, invasion, and metastasis. E-cadherin suppresses liver metastasis formation, while high IL-6 levels in breast cancer liver metastases inhibit function of E-cadherin