Molecule secreted by cancer-associated fibroblasts promotes anticancer drug resistance

August 21, 2020

A joint project led by Kumamoto University (Japan) has discovered a new mechanism for anticancer drug resistance in gastric cancer. Researchers found that the Annexin A6 molecule contained in extracellular vesicles (EVs) is secreted by cancer-associated fibroblasts (CAFs) and taken up by gastric cancer cells, resulting in resistance to anticancer drug treatments. This finding creates new avenues for novel drug development targeting Annexin A6 and cancer-associated fibroblasts (CAFs).

Gastric cancer is the second most common cancer in Japan. For advanced gastric cancer in particular, treatment involves various anticancer drugs but too often they do not sufficiently improve medical conditions.

The tumor microenvironment is the area around cancer cells that consists of various cells and support systems, both physical and biochemical. Within this microenvironment, CAFs are known to enhance the malignant transformation of cancer by secreting various factors.

"Our research found that higher amounts of CAFs in tissues resulted in worse conditions for gastric cancer patients. This was also true in patients with advanced gastric cancer who had been treated with anticancer drugs," said Dr. Tomoyuki Uchihara. "Based on this, we wondered if there was some factor derived from CAFs that induced anticancer drug resistance."

In a cell experiment approximating the conditions of a living human body, gastric cancer cells that were cultivated with a culture of CAFs acquired anticancer drug resistance. Through gene expression analysis in gastric cancer cells, researchers discovered that CAF-EV derived Annexin A6 played an important role in gastric cancer cell resistance to anticancer drugs. EVs are tiny sacs of material surrounded by lipid bilayers (membranes) that are released from cells and involved in cell-to-cell information transmission. The researchers also found that Annexin A6 is rarely expressed in gastric cancer cells themselves and is usually present only in CAFs.

This shows that Annexin A6 is involved in the acquisition of anticancer drug resistance by being taken up by gastric cancer cells via EVs. Further experimental results have suggested that Annexin A6 contributes to anticancer drug resistance by stabilizing the cell adhesion molecule "β1 integrin" on the gastric cancer cell membrane and activating FAK-YAP signaling after being taken up by gastric cancer cells.

"Here we showed that CAF-derived Annexin A6, which surrounds gastric cancer cells, causes resistance to anticancer drug treatments," said research team member, Associate Professor Takatsugu Ishimoto. "As the research progresses, new drugs targeting Annexin A6 and CAFs in gastric cancer are expected."
-end-
This research was posted online in "Cancer Research" on 30 June 2020.

[Source] Uchihara, T., Miyake, K., Yonemura, A., Komohara, Y., Itoyama, R., Koiwa, M., ... Ishimoto, T. (2020). Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance. Cancer Research. doi:10.1158/0008-5472.can-19-3803

Kumamoto University

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.