Researchers at the Department of Radiation Oncology and Molecular Radiology at the Kimmel Cancer Center at Johns Hopkins University have discovered a lipid-modulating protein that transfers a substance that researchers call “superpower” to prostate cancer cells, allowing them to spread malignantly.

 

In studies of human prostate cancer cells and stromal cell lines, when the lipid regulatory protein called CAVIN1 was removed from stromal cells (connective tissue cells in and around the tumor), the cells no longer used lipids. Instead, cancer cells enjoy the oil in the environment, using it as fuel, including the hormones needed to make cancer. This discovery was recently published in the journal Molecular Cancer Research.

 

Dr. Marikki Laiho, director of the Department of Molecular Radiation Science at Johns Hopkins University School of Medicine, professor of radiation oncology and molecular radiation science, and senior author of the study, said: “We know that aggressive behavior tumors, such as rapid growth and metastasis, do not happen alone, so we want to find out the role of the tumor microenvironment in promoting the proliferation of cancer cells, especially the interaction between prostate tumor cells and stromal cells.”

 

 

In human cell line experiments, when the researchers removed CAVIN1 from fibroblast stromal cells, the stromal cells no longer used lipids, but the lipids remained in the environment, which surprised the researchers that they became the buffet for the cancer cell. In each prostate cancer cell line tested, the authors found that tumor cells generally have an appetite for lipids, which can be used to promote growth, strengthen the protective membrane around the cells, synthesize proteins, and enable testosterone to support cancer growth.

 

“As a result, tumor cells are more aggressive, showing aggressive and metastatic behavior,” said the study’s first author Jin-Yih Low. “As long as they can reach the lipid, the tumor cells can get more energy. The tumor is still the original tumor, but the behavior of the tumor has changed.”

 

In addition, when stromal fibroblasts do not use lipids, they have changed and began to secrete inflammatory molecules, which changing the tumor microenvironment. Inflammation is a feature that has long been thought to promote cancer.

 

To confirm their findings, the researchers conducted similar experiments in a mouse model, implanting prostate cancer cells and stromal cells in the prostate of mice, and comparing the behavior of tumors with or without CAVIN1 function in stromal cells. Although the presence or absence of CAVIN1 will not affect the growth rate of the tumor, the lack of CAVIN1 will cause the tumor to spread. The metastasis rate of mice whose tumors do not express CAVIN1 increased by 2 to 5 times. The lipid and inflammatory cells of these tumors also increased by 40 to 100 times.

 

Laiho called these findings shocking. “We suspect that CAVIN1 is important, but we don’t realize how important it is. The microenvironment is important, and the amount of fat is very important. Just by switching cells from low-fat levels to high-fat levels, it has caused malignant metastases.”

 

The researchers said that the absence of CAVIN1 in tumor cells may be used as a biomarker to alert clinicians to the risk of metastasis. Interventions are being studied, but they are challenging because all cells require lipids. Any treatment aimed at suppressing lipids must specifically target cancer cells. Ongoing research aims to better understand the inflammatory process and ways to prevent it from accelerating the spread of cancer. For example, the researchers wanted to understand why inflammation attracts macrophages to further aggravate the inflammatory process, but does not attract beneficial T cells to fight cancer, and whether lipid cells can send signals to affect immune checkpoints–the immune system’s on and off switches.

 

CAVIN1 was first discovered in human lipodystrophy syndrome, a disease that prevents the absorption of lipids and prevents patients from making fat cells, thus putting them at risk of diseases such as cardiovascular disease and diabetes.

 

 

Reference

Loss of lipid-regulating gene fuels prostate cancer spread

Jin-Yih Low et al. Stromal CAVIN1 controls prostate cancer microenvironment and metastasis by modulating lipid distribution and inflammatory signaling， Molecular Cancer Research (2020). DOI： 10.1158/1541-7786.MCR-20-0364