Pancreatic cancer is one of the most malignant tumors. It is called “the king of cancer” because of its low survival rate and extremely short survival period. It is usually asymptomatic in the early stage and often spreads to the whole body when it is diagnosed.
Pancreatic cancer is difficult to diagnose and difficult to treat, and is closely related to its special tumor microenvironment. Unlike other cancers, pancreatic tumor cells are encapsulated in a “protective layer” composed of interstitial cells and their secreted intercellular matrix. This not only increases the difficulty of disease detection, but also allows pancreatic cancer cells to evade attacks by chemotherapy drugs and the immune system. Patients are therefore resistant to a variety of anticancer drugs.
The protective interstitial cell layer is mainly composed of pancreatic stellate cells, which can account for up to 90% of advanced pancreatic tumors. Previous studies have shown that if the pancreatic stellate cells are killed, the tumor will get worse. Therefore, scientists have always wanted to know how they collude with cancer cells.
On April 17, a study published in the journal Nature, an international team of scientists from the Salk Institute of Biology and China Southern University of Science and Technology found that leukemia inhibitors were secreted by stellate cells. The signaling protein of (Leukemia inhibitory factor, LIF) may be the Achilles heel of pancreatic cancer.
In fact, very early on, researchers suspected that stellate cells communicated with tumor cells through specific signaling proteins, but they never knew which one. Professor Tony Hunter of the Salk Institute believes that understanding the communication network between cancer cells and stellate cells may help develop more effective pancreatic cancer therapies and tools for earlier diagnosis.
In this study, Professor THunter first developed an integrated proteomic analysis strategy for studying intercellular signal transduction in the tumor microenvironment to analyze proteins secreted from stellate cells.
It has been found that pancreatic stellate cells, which are normally dormant in normal tissues, become active in order to form a protective “shell” for the tumor. The activated stellate cells secrete LIF, which transmits stimulation signals to adjacent tumor cells, thereby promoting the development of pancreatic cancer.
LIF is a key paracrine factor
To assess whether LIF could serve as a potential therapeutic target, the researchers investigated the effects of blocking or disrupting LIF function on tumor growth. In the KPC mouse model of pancreatic cancer, the selective knock-out of LIF receptor membrane protein LIFR can slow down the malignant development of pancreatic tumors, prolong the survival time of mice, and enhance the efficacy of the chemotherapy drug gemcitabine. In addition, LIF antibody binding to chemotherapy can also significantly prolong the survival of pancreatic cancer mice. According to Professor Hunter, this suggests that LIF antibodies are expected to be used in combination with other therapies to treat pancreatic cancer.
LIF antibodies provide therapeutic benefit to pancreatic ductal adenocarcinoma by affecting cancer cell differentiation
In addition to examining the effects of blocking LIF on mice, the researchers also examined the levels of LIF in tumor tissue and blood in human pancreatic cancer patients. The results showed that patients with tumors and blood contained high levels of LIF, and the level of LIF was significantly correlated with tumor progression and patient response to chemotherapy.
In pancreatic cancer tissues, LIF (green) mainly expressed in activated pancreatic stellate cells appears together with immune cells (purple) and cancer cells (yellow).
LIF is a very important factor in the embryonic phase, helping stem cells maintain their developmental potential, but usually disappears in adulthood. In this study, both mouse models and human pancreatic cancer analysis showed that high levels of LIF were significantly associated with tumor cell status and response to chemotherapy. This means that LIF may be a useful biomarker for faster and more effective diagnosis of pancreatic cancer (currently, the only FDA-approved pancreatic cancer biomarker is a carbohydrate antigen called CA19-9); At the same time, it may also be a good target for subverting the treatment of pancreatic cancer.
Based in part on the discovery by Professor Hunter, a Canadian company called Northern Biologics has launched Phase I clinical trials of LIF antibodies for advanced pancreatic cancer and other types of cancer.
“Our research results have a direct impact on human fatal cancer, which is very enjoyable.” Professor Hunter said.