Science Advances: Mechanisms by which metastatic cancer cells infiltrate the liver

About 90% of cancer-related deaths are due to metastasis
as the cancer spreads and new tumors form.
The liver is considered the organ most prone to metastases: 5-year survival rates after surgery to remove liver metastases are as low as 30-50%, so there is an urgent need to develop treatments
to prevent liver metastases.

A team of researchers, including Osaka City University School of Medicine graduate students Truong Huu huang and Norifumi Kadawa, and Misako Matsubara, associate professor at the Graduate School of Veterinary Science, have discovered another pathway for liver metastasis, suggesting that cancer cells invade through the formation of endothelial intracellular spaces and elucidate the relevant molecular mechanisms
.
Their findings are expected to lead to the development of
drugs to prevent and treat metastatic liver cancer.

Metastatic cancer cells are known to alter the microenvironment of liver cells, thereby facilitating metastasis, but the extent of these interactions has not been adequately studied
.
Cancer cells carried in the blood come into contact with hepatic sinusoidal endothelial cells (LSECs), which line the blood vessels of the liver and form a protective barrier
.
LSEC is responsible for the detoxification function of the liver, it has many small pores, liquid components of the blood and small particles (not cancer cells) can enter the liver
through these pores.
LSEC is often exposed to toxic substances carried by the blood, which, under stressful conditions, can damage these small pores; This leads to the formation of larger intracellular spaces in LSECs, weakening the protective barrier
.
This led the team to suggest that the intracellular space of LSECs may be involved in
liver metastasis.

By injecting cancer cells into the spleen, the team established a mouse model of liver metastasis and performed omics analysis to observe changes in
LSECs.
They found that when cancer cells metastasize from the spleen to the liver, they induce LSECs to produce a variety of proteins
.
The expression of one of these proteins, matrix metalloproteinase 9 (MMP9), in LSECs leads to the formation
of intracellular spaces.

In addition, using electron microscopy and 3D tomography reconstruction, the researchers found that cancer cells project them directly into the intracellular space of LSECs, allowing them to penetrate into liver tissue
.
They found that the number of intracellular spaces of LSECs was positively correlated
with the number of newly formed metastatic liver tumors in mice.
However, treating mice with MMP9 inhibitors prevented the formation of new tumors, suggesting that MMP9 is a promising therapeutic target to prevent liver metastasis
.

Professor Matsubara concluded: "In this study, we discovered a novel phenomenon associated with metastasis: cancer cells induce LSEC intracellular space formation and penetrate into the liver
through these gaps.
Based on these results, we are continuing to research and develop new treatments for liver metastases, targeting
intracellular space formation in LSECs.
”

Journal Reference:

1. Truong Huu Hoang, Misako Sato-Matsubara, Hideto Yuasa, Tsutomu Matsubara, Le Thi Thanh Thuy, Hiroko Ikenaga, Dong Minh Phuong, Ngo Vinh Hanh, Vu Ngoc Hieu, Dinh Viet Hoang, Hoang Hai, Yoshinori Okina, Masaru Enomoto, Akihiro Tamori, Atsuko Daikoku, Hayato Urushima, Kazuo Ikeda, Ninh Quoc Dat, Yutaka Yasui, Hiroji Shinkawa, Shoji Kubo, Ryota Yamagishi, Naoko Ohtani, Katsutoshi Yoshizato, Jordi Gracia-Sancho, Norifumi Kawada.
   Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms.
   Science Advances, 2022; 8 (39) DOI: 10.
   1126/sciadv.
   abo5525