Mucinous Cancer of the Ovary & Natural Killer Cells
Mucinous Ovarian Cancer ( MOC) is a rare subtype of epithelial ovarian carcinoma. It has to be addressed differently during therapy. There is a need to understand its pathological features and genomic profile to manage it in a better manner.
About 80% of ovarian mucinous carcinomas are metastatic, mostly in stage I. Common primary sites for metastasis are the gastrointestinal tract (45%), pancreas (20%), cervix, and endometrium (18%), and breast (8%). Accurate diagnosis of primary mucinous ovarian carcinoma requires careful examination due to its similarity to other mucinous carcinomas, especially colorectal carcinoma. Recognizing microscopic features and understanding the immunohistochemistry profile are crucial for proper treatment and prognosis.
MOC (Mucinous Ovarian Carcinoma) is the most common subtype in women under 40. Unlike HGSC (High-Grade Serous Carcinoma), MOC isn’t linked to typical risk factors, except for a possible association with tobacco smoking. While most HGSC cases are found at an advanced stage, MOC is often diagnosed at stage 1 in 80% of cases.
Chemotherapy is typically given for stage II MOC and beyond, following standard gynecology protocols, though gastrointestinal regimens are also used. Given the multiple molecular alterations associated with MOC, targeted therapy may be a promising approach for treatment.
Ovarian cancer affects around 22,000 women in the US every year, currently, there are limited treatment options which is why there is a need for better therapies to be tried and discovered.
The immune system plays a crucial role in responding to this form of cancer. Immunotherapies, making use of antibodies or T cells, are some of the latest solutions to solving the symptoms of ovarian cancer. However, it poses a huge challenge when it comes to side effects.
Tissue Development of Mucinous Ovarian Carcinoma:
The normal mucinous epithelium has three types of mucus-secreting cells found in the stomach, endocervix, and intestine. However, normal ovarian tissues do not contain these cells. The development of MOC (Mucinous Ovarian Carcinoma) is explained by several theories:
- Mucinous Adenoma Carcinoma Sequence
- Development occurs in a stepwise fashion.
- Mucinous cystadenoma and mucinous borderline components coexist with carcinoma.
- Carcinoma progresses from benign epithelium to borderline tumor to invasive carcinoma.
- KRAS mutation happens early, while TP53 mutation and HER2 amplification occur later and are exclusively found in mucinous carcinoma.
2. Germ Cell Origin
- Proposed due to the association with mature teratoma in 5% of cases.
- Presence of gastrointestinal-type cells and markers, although most MOCs lack teratomatous components.
3. Mucinous Metaplasia
Suggested as the ovarian surface epithelium or cortical inclusion cysts undergo mucinous transformation.
Mucinous metaplasia is a rare change in the endometrial epithelium, usually linked to high estrogen levels or hormone replacement therapy. It can show simple mucinous epithelium resembling the endocervix or more complex mucinous growth patterns.
4. Association with Endometriosis
MOCs are often endocervical-like or Mullerian mucinous tumors.
5. Association with Brenner Tumors
Mucinous epithelium, especially the intestinal type, may develop from transitional cells or metaplasia at the fallopian tube-peritoneal junction.
These theories offer different perspectives on the origins and development of MOC.
Understanding the Role of Natural Killer Cells for Fighting Ovarian Cancer
Natural Killer Cells ( NK) is seen as a holy grail, medical researchers are currently exploring the possibility of using it to combat immune escape and tumor relapse. This is because NK cells are effective in the surveillance of tumors, regulated by various receptors, and have the potential to influence the tumor environment leading to effective immune control of ovarian cancer- one of which is Mucinous Ovarian Cancer.
NK cells, or natural killer cells, are a type of white blood cell found in the bloodstream, making up 5–10% of lymphocytes. They don’t require prior exposure to target cells and are effective against tumors. Derived from bone marrow, NK cells are closely related to T cells, sharing abilities to release substances for direct target cell destruction. They induce target cell death through various pathways and release inflammatory cytokines. NK cells can be categorized based on surface markers, with CD56bright/CD16– primarily producing cytokines and CD56dim/CD16+ engaging in cytotoxicity in tissues,
NK cells don’t directly detect antigens like T and B cells. Instead, they identify potential targets based on stress-induced signals, which occur when cells experience DNA damage, heat shock, or exposure to certain environmental factors like cytokines. To prevent attacking healthy cells, NK cells are influenced by both activating and inhibitory signals. The balance of these signals determines how NK cells respond to a potential target.
Mechanism of how NK Cell recognizes cancer
Natural Killer (NK) cells have a special ability in cancer immunotherapy: they can target and destroy tumor cells without prior sensitization. Discovered in 1975, NK cells recognize tumor cells without specific antigens, relying on a balance between activating and inhibitory signals. Receptors like killer immunoglobulin-like receptors (KIRs) and NKG2A interact with major histocompatibility complex (MHC) molecules, sending inhibitory signals to prevent NK cell activation against healthy cells. However, when MHC expression is lacking, NK cells activate through a “missing self-recognition” mechanism, leading to the elimination of tumor cells.
Recent studies show that NK cell activation isn’t solely triggered by MHC absence. Activated NK cells express additional receptors like DNAM-1, NKG2D, and natural cytotoxicity receptors (NCRs), binding to stress-induced ligands on tumor cells. This “induced self-recognition” mechanism expands NK cell activation. NK cells with CD16 can also activate in response to tumor cells coated with antibodies, leading to antibody-dependent cellular cytotoxicity (ADCC). When activating signals outweigh inhibitory ones, NK cells execute cytotoxicity through mechanisms like granule release and apoptosis induction. Activated NK cells also produce pro-inflammatory cytokines, enhancing anti-tumor immune responses. This complex process highlights the multifaceted role of NK cells in cancer immunotherapy.
NK cells prevent the spread of ovarian cancer cells and have a positive therapeutic impact according to studies:
The findings indicate that introducing NK cells could be a promising therapeutic approach. The study involved isolating and culturing human ovarian cells, injecting them into mice, and treating them with NK cells. Results showed that NK cells inhibited ovarian cancer cell metastasis in mice.
Additionally, NK cells activated the immune system, limiting tumor growth both in the lab and in a mouse model.
The study suggests that NK cells, through their cytotoxic activity, can prevent cancer cell migration and invasion, reducing the risk of systemic metastasis.
The introduction of NK cells also induced apoptosis and enhanced immune responses in the mice, ultimately improving their survival rate.
In conclusion, the study proposes that NK cell immunotherapy has the potential to be an effective strategy against ovarian cancer, inhibiting metastasis and enhancing survival rates.
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