Save our souls from the enemy within: A battle against oral cancer

I was getting ready to leave to lab at 9 am. The mobile started ringing and the Caller ID displayed the name of my school friend, Koushik Das.

“Hello!”

“Hi Tanaya! Are you free?”

“Yup! Tell me how are you? All good?”

There was a moment of silence, and then he said “No! Mother is not well, it’s stage IV oral cancer! She has been admitted at the hospital and is critical. Too many tubes sticking out of her body. Can anything be done? I just don’t know what to do.”

“Koushik please calm down. Tell me the address and the visiting hours, I will visit today.”

I took a note of the hospital address and the visiting hours. I was in the 2nd year of my PhD and was trying hard to contribute new information to the immense field of cancer biology. I had started some pilot experiments on cancer cells in the lab. I work on a protein called SMAR1 that helps get rid of cancerous cells. In technical terms, we call such a protein a tumour suppressor. My aim was to identify the molecular mechanism(s) by which SMAR1 was acting. Incidentally, I was studying the function of SMAR1 in cancers of the mouth or oral cancer.

Oral cancer or mouth cancer refers to a cancer that develops in any part of the mouth. It can occur under the tongue (floor of the mouth), roof of the mouth, lips, gum, tongue, and inner linings of the cheek. Oral cancer is categorized under head and neck cancers as they are often treated similarly. Cancers occur when abnormal cells grow. Cells contain DNA that gives instructions to the cells. But when harmful DNA changes occur (mutations), cells get the instruction to divide and grow continuously leading to the formation of a lump or tumour. Over time, the tumour cells spread to head, neck, and other internal body sites. Regular use of tobacco in the form of cigarettes, cigar, chewing of tobacco, heavy alcohol consumption, infection with human papilloma virus (HPV) or a weakened immune system can lead to oral cancer development. Some of the symptoms are as follows (1):

  • Ear or mouth pain
  • White (leukoplakia) or reddish (erythroplakia) patches inside oral cavity.
  • A lip or mouth sore that does not heal.
  • Lump or growth inside mouth
  • Pain or difficulty in swallowing

There are millions of patients worldwide losing the battle to oral cancer. According to the National Cancer Registry Programme 2020 report (2) released by the Indian Council of Medical Research (ICMR) there are 13.9 lakh cancer cases in India which is predicted to rise to 15.7 lakh by 2025. As per the data, tobacco related cancer is estimated to account for 27.1% Of the total cancer load inIndia. It is therefore important to spread cancer awareness in general with emphasis on tobacco related cancers. Upon reaching the hospital I went straight to the 4th floor and found Koushik sitting just outside the cabin staring blankly into the corridor. I gently patted on his shoulder. He was startled at first but then seeing me he was happy.

“Can I visit her?”

He nodded.

Entering her cabin filled me with sadness. She was on IV drips, asleep. Cables connected to her chest were feeding information into the monitor, that displayed her vital parameters. She appeared very pale and skinny. I did not wake her up and silently came out of her cabin.

“Did she not have any symptoms initially? Oral cancer is usually curable if detected at anearly stage. Was she in the habit of chewing betel quid, areca nut or any form oftobacco?”

“Yes, she regularly took arecanut. She had a mass on the floor of her mouth, but it was painless. Lately, there was bleeding and problems with swallowing. She lost a considerable amount of body weight too. There has been negligence onmy part too. I wish I took her to the doctor earlier. You are doing your PhD on cancer; can you not help me?”

I said “There are several treatment options available now. For example, chemotherapy that uses cell killing (cytotoxic) drugs, radiotherapy which uses high energy beams to kill the dividing cancer cells or targeted therapy that can specifically stop the function of a particular protein essential for cancer cell survival and growth. Lately immunotherapy (3) is also being used for the treatment of advanced cancers where the body’s own immune system is used to kill the cancer cells by interfering with the function of certain bodily proteins that hold the immune system in check.”

“What has the doctor suggested?”

Koushik said “Doctor has suggested chemotherapy.”

“Okay. Let’s hope for the best.”

After my visit, I returned home with a burning question- will my work be useful?

In lab, we were trying to formulate a biologically active extract from broccoli. Broccoli belongs to the cruciferous family of vegetables which is rich in several useful bioactive molecules. One of those is sulforaphane which has potent anti- cancer activities. Interestingly, this compound stabilized SMAR1 (4). Thus, we thought of exploring how it might be used for oral cancer treatment. One might ask, why not simply consume broccoli instead of formulating something out of it? We are all different physiologically in terms of finer bodily mechanisms and/or our ability to digest and absorb nutrients. So, it is essential to make an enriched formulation that delivers sufficiently high amounts of sulforaphane and other phytochemicals. We tested different extraction methods and determined which one was best at stabilizing SMAR1 and other tumour suppressor proteins.

I used to be in touch with Koushik and visit her often. But with time her cancer started showing resistance to chemotherapy and eventually she left us.

Translational research and basic science should go hand in hand to genuinely address a severe disease like oral cancer. After finalizing the formulation, we started testing it on oral cancer cells. There was a slowing down of cell division and SMAR1 stabilized alongside reduction in other cancer causing (oncogenic) pathways.

During this time there was a breakthrough study published in the prestigious journal Science (5) from Prof. Paoli Pandolfi’s lab that connected a bioactive compound Indole-3-carbinol (I3C) found in cruciferous vegetables to another important tumour suppressor PTEN. I3C stabilized PTENin a prostate cancer mouse model. This further substantiated our idea. We next developed a mouse model of oral cancer and tested our extract to test its ability to inhibit cancer development. Using immunohistochemistry, a technique widely used to look at the proteins in a tissue, we checked SMAR1 levels. It was stabilized! We checked other marker proteins too to confirm our findings. We are in the process of identifying other bioactive molecules of broccoli to test their ability to stabilize SMAR1 and other important tumour suppressor proteins.

In vivo testing of enriched broccoli extract

Cancer is a multi-factorial disease and SMAR1 is one of the several key tumour suppressors important to curb the disease progression. There are multiple oncogenicpathways which are simultaneously activated leading to cancer. So, it is important to suppress as many oncogenic pathways as possible. An enriched extract of essential anti-cancer compounds in sufficient amounts to be effective is required. An enriched extract containing the different compounds, working in synergy, will require lower dose for each individual component. This will lead to lower side effects as compared to other chemotherapeutic drugs.

Early screening and intervention are always helpful but unfortunately due to a lack of awareness, oral cancer cases are frequently diagnosed at an advanced stage leading to poor disease outcomes. Translational research coupled with basic research is the need of the hour.

References:

  1. Mouth cancer – Diagnosis and treatment – Mayo Clinic
  2. https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx
  3. Mohan, Sunil Paramel et al. “Immunotherapy in Oral Cancer.” Journal of pharmacy & bioallied sciences vol. 11,Suppl 2 (2019): S107-S111. doi:10.4103/JPBS.JPBS_31_19
  4. Traka, M., Gasper, A. V., Smith, J. A., Hawkey, C. J., Bao, Y., &Mithen, R. F.(2005). Transcriptome analysis of human colon Caco-2 cells exposed to sulforaphane. The Journal of nutrition, 135(8),1865-1872.
  5. Lee,Y.R.,Chen,M.,Lee,J.D.,Zhang,J.,Lin,S.Y.,Fu,T.M.,…&Zhang,Y.(2019). Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science,364(6441).

 

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