There are thousands of protein molecules in our bodies required to carry out normal biological processes. Many of these proteins are signaling proteins called cytokines, which signal or “talk” to other molecules and provide necessary instructions for development and cell growth. One such cytokine is leukemia inhibitory factor (LIF).

LIF was originally identified as a key factor that stops the proliferation, or multiplication, of a mouse myeloid leukemia cell line. Although the protein was named “leukemia inhibitory factor” due to this original observation, LIF has since been found to play many diverse roles across different cell types and tissues.

How Does LIF Work?

Cytokines function by interacting with partner proteins known as receptors. This interaction allows cell proliferation and other biological processes to occur. LIF is similar to another cytokine known as interleukin-6 (IL-6). Although these two proteins are closely related, they have distinct roles and “talk” to different receptors. The partner receptor for LIF is the LIF receptor (LIF-R).

LIF can come in contact with LIF-R and lead to activation of a cell signaling pathway, a chain reaction of other protein interactions that ultimately send instructions to cells for growth and survival. Signaling pathways that involve LIF include MAP kinase, STAT-3, and PI(3)-kinase (PI3K). LIF receptors are found in many different types of cells and tissues, which allows LIF to activate the various signaling pathways and cause a wide array of effects in the body, including in reproduction, stem cell differentiation, and cancer.

The Role of LIF in Reproduction

Research in genetic animal models has revealed that LIF has important functions in the reproductive process, as LIF is responsible for maintaining the integrity of the embryo, known as a blastocyst, during early development. Specifically, in mice that lack LIF, blastocyst implantation fails to occur in the uterus and results in infertility.

Moreover, some of these functions have been defined as nonredundant. Redundancy is a biological phenomenon in which different molecules can share the same function. That way, if one protein has a mutation that causes it to no longer work, others can serve as a backup that performs the same job. LIF is nonredundant in some of its roles in reproduction, which means that it is required for normal development of an embryo.

The Role of LIF in Stem Cells

In addition to its role in reproduction, LIF is also important for maintaining the embryonic stem cell population as discovered using genetic animal models and cell lines.

Although mature cells are specific to a certain organ (brain cells are unique to the brain, skin cells are unique to the skin, and so on), embryonic stem cells have the ability, known as pluripotency, to multiply and become any specific cell type. The process of a stem cell becoming an organ-specific cell is known as differentiation. LIF “talks” to other protein molecules, and researchers have observed that it sends signals that instruct mouse embryonic stem cells to postpone differentiation and continue multiplying.

Interestingly, the role of LIF in human embryonic stem cells is a bit more complex. Although not solely responsible for differentiation, signaling pathways that involve LIF, such as the STAT-3 and MAPK pathways, have varying effects on differentiation in human cells. The role of LIF — whether direct or indirect — in differentiation and stem cell pluripotency indicates that LIF plays a crucial role in early development.

The Connection Between Stem Cells, LIF, and Cancer

Although cancer is a group of devastating diseases, the underlying biology is the same as many normal processes. For example, the normal mechanisms in stem cell biology promote cell proliferation (growth). In cancer, these processes have been “hijacked,” meaning they have been turned on at the wrong time or in the wrong organ. This leads to improper growth of cells and tumor formation.

Because LIF has been shown to have a role in stem cell proliferation and differentiation, it has also been studied for its role in the progression of certain cancers due to overlapping biological mechanisms.

LIF Activity in Cancer Development

LIF plays an important role in normal biological processes and is also involved in cancer progression. Despite being originally identified for its role in a myeloid leukemia cell line (and subsequently named for this function), LIF generally appears to be a major player when it comes to solid tumors rather than blood cancers.

The disease that most commonly involves LIF is pancreatic cancer. It has been shown to promote the spread of pancreatic cancer, and preventing LIF signaling activity slows the growth of pancreatic cancer cells. LIF also promotes the spread of other cancers, including melanoma and soft tissue sarcomas that affect the bone marrow.

Interestingly, LIF appears to have different effects in different cancer types. Rather than promoting the spread of cancer, LIF and LIF-R have been shown to prevent the growth of breast cancer cells. Anti-tumor effects of LIF have also been observed in stomach cancer cells. Because LIF functions by signaling to a variety of other proteins in different cell types, its role in cancer appears to depend heavily on the biological context.

LIF as a Prognostic Marker for Cancer

Identifying biological molecules that indicate disease prognosis (outlook) can be helpful for cancer treatments. If levels of a certain protein can be measured and used as a marker of poor prognosis or improved prognosis for a person with cancer, it can help to evaluate whether a cancer treatment is working.

Due to its role in various cancers, LIF has been explored as a marker for predicting treatment outcomes. LIF has evidence of being an indicator of both improved outcomes or poor outcomes, depending on the disease.

Can LIF Be Targeted To Treat Cancer?

Due to its apparent importance in the progression of various cancers, LIF is being explored as a potential therapeutic avenue to treat certain types of cancer. LIF is often overexpressed in cancer, meaning that the number of LIF molecules in the body is higher than what it normally should be. In cancers with too much LIF, blocking its activity may prove effective against slowing cancer growth. Although this approach has been explored experimentally using genetic mutation, a drug designed to target and inhibit LIF would present a new opportunity for cancer treatment.

What Does the Future Hold for LIF Research?

Because LIF has several different functions in various biological contexts, the exact role it plays in cancer development is still being explored across different diseases. One thing is clear, however: the name “leukemia inhibitory factor” does not tell the whole story of this protein. LIF has key responsibilities in embryonic development and is involved in processes in many cancers. As a cytokine, LIF can “talk” to other proteins and cause a wide range of effects. Further studies are underway to better understand the role LIF plays in cancer progression and its potential as a therapeutic target to treat certain forms of cancer.

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