Targeting folate receptors for cancer treatment | Jabar Post Indonesia – This time JabarPost.Net will discuss about Mesothelioma.
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Targeting folate receptors for cancer treatment | Jabar Post Indonesia
Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining of the abdomen and rarely the sac surrounding the heart, or the sac surrounding the testis may be affected. Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. These symptoms typically come on slowly.
More than 80% of mesothelioma cases are caused by exposure to asbestos. The greater the exposure the greater the risk. As of 2013, about 125 million people worldwide have been exposed to asbestos at work. High rates of disease occur in people who mine asbestos, produce products from asbestos, work with asbestos products, live with asbestos workers, or work in buildings containing asbestos. Asbestos exposure and the onset of cancer are generally separated by about 40 years. Washing the clothing of someone who worked with asbestos also increases the risk. Other risk factors include genetics and infection with the simian virus 40. The diagnosis may be suspected based on chest X-ray and CT scan findings, and is confirmed by either examining fluid produced by the cancer or by a tissue biopsy of the cancer.
Prevention centers around reducing exposure to asbestos. Treatment often includes surgery, radiation therapy, and chemotherapy. A procedure known as pleurodesis, which involves using substances such as talc to scar together the pleura, may be used to prevent more fluid from building up around the lungs. Chemotherapy often includes the medications cisplatin and pemetrexed. The percentage of people that survive five years following diagnosis is on average 8% in the United States.
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Advancements in immunotherapy has lead to interested in the tumour associated antigen Folate receptor alpha (FRa). FRa is overexpressed in ovarian, breast and lung cancer.
Folate is required for rapidly dividing cells for one carbon metabolism and DNA biosynthesis.
Folate is transported into cells by 3 routes, the main being the reduced folate carrier (RFC), which is ubiquitously expressed.
The second is the proton coupled folate transporter (PCFT) and the third is by folate receptors.
FRa distribution is restricted to low levels on the apical surfaces of the kidneys, lung and choroid plexus.
FRa is thought to internalise folate by a non classical lipid raft mediated endocytosis (potocytosis). Folate binds to FRa which then is internalised into an intracellular vesicle, these then uncoat and join to form an early endosome that is then acidified and fuses with lysosomes to release the folate.
FRa may then translocate to the nucleus to act as a transcription factor to regulate the expression of cancer genes.
Ovarian cancer cells transfected with a single chain antibody targeting FRa impaired tumour cell proliferation and colony formation.
Folate uptake can promote cancer cell proliferation, migration and adhesion by downregulating E cadherin increasing cell motility and metastasis.
The absence of E cadherin is correlated with reduced patient survival in ovarian carcinomas.
FRa has been shown to inhibit caveolin-1 supporting anchorage independent growth and proliferation of tumour cells and promoting cancer progression.
FRa overexpression has been reported to associate with STAT3 signalling. Its demonstrated that folate binding to FRa can induce STAT3 activation via GP130 mediated JNK dependent process.
FRa overexpression is reported to be expressed in metastatic foci and recurrent tumours, even in microenvironments with limited folate availability.
In all tissues (except the kidneys) the receptor is found on the apical surface, out of direct contact with folate in circulation.
FRa in the kidney tries to retrieve folate from urine but folate is not retained in the kidneys, with no lethal toxicities in rodents or humans treated with FRa targeting agents.
In ovarian cancer, FRa is overexpressed in 80% of epithelial ovarian cancers (EOCs) and its expression has been shown to significantly correlate with histological grade and stage.
FRa may facilitate resistance to chemotherapy in ovarian carcinoma patients with higher tissue FRa associated with lower response rates to chemotherapeutic agents.
FRa tumour surface expression does not differ between paired samples, before and after chemotherapy. Chemotherapy does not affect antigen expression and FRa positivity can be used to detect recurrent disease.
Non small cell lung cancer NSCLC accounts for about 80% of lung cancers the prognosis is poor with a 5 year all stage survival rate of 21%.
Higher FOLR1 gene expression levels correlated with significantly higher 3 year disease free survival DFS and OS rates.
Overexpression of FRa has been detected in up to 72% of patients with an uncommon and aggressive thoracic cancer, pleural mesothelioma.
High FRa tissue expression as observed in 74% of estrogen receptor progesterone receptor negative breast cancers.
Oestrogen downregulates the expression of FRa with a negative correlation between tumours that express ER and those which express FRa.
Tamoxifen binds and inhibits the ER function causing a rise in FRa expression.
Triple negative breast cancer TNBC which is characterised by the lack of ER, PR and HER2 representing only 10-15% of all breast carcinomas.
It results in a disproportionate number of metastatic disease and deaths due to its aggressive natural history and lack of available therapies.
High FRa expression was seen in 80% of TNBC cases.
Overepression of FRa was significantly associated with poorer disease free survival.
Correlation of high FRa expression between primary, local and distant metastatic disease could potentially be treated with anti FRa therapies when the primary cancer shows overexpression.
Soluble RRa (sFRa) is reported to be low or undetectable in normal human sera
Patients with serous and non serous ovarian carcinoma have demonstrated elevated levels of sfrA compared to healthy individuals.
The use of sFRa may therefore work as a diagnostic biomarker in early stage I/II disease.
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