There are two types of cancer treatment:
- Local therapy: Treatments directed at the cancerous anatomic areas, such as surgery, radiation therapy, and hyperthermia therapy.
- Systemic therapy: The use of drugs, introduced into the blood stream, and therefore in principle is able to address cancer at any anatomic location in the body, e.g., hormone therapy and chemotherapy.
Chemotherapy is a type of systemic treatment for cancer which uses cytotoxic drugs, i.e., intracellular poisons, to shrink cancerous tumors by inhibiting mitosis, the process of cell division, eventually leading to cell death. The problem is the cytotoxic drugs don’t just kill cancer cells but also damage normal cells, especially cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow, digestive tract and hair follicles. This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).
But a new study has found something even worse and truly perverse about chemotherapy: Although it shrinks cancerous tumors, chemotherapy actually spreads (or metastasizes) cancer throughout the patient’s body.
The team of 16 scientists — led by Dr. George S. Karagiannis, a post-doc at the Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York — published their findings, “Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism,” in the peer-reviewed journal, Science Translational Medicine, vol. 9, issue 397, July 5, 2017.
Although the study was conducted on breast cancer, logically the findings should apply to other cancers as well, especially in view of the fact that breast cancer is one of the most common types of (cancerous) tumors.
Karagiannis et al. focused their study on a group of cells called tumor microenvironment of metastasis (TMEM), which serve as gateways for cancerous tumor cells to enter the vasculature or circulatory system.
The scientists discovered that, in addition to killing tumor cells, chemotherapy treatment can increase the amounts of TMEM, leading to increased intravasation — the entrance and circulation of foreign material (cancerous cells) into the bloodstream.
Here’s the article’s Abstract:
Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression* and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.
*Note: “Mena expression” refers to the Mena protein, a key potentiator and modulator of cellular migration and, therefore, is a prometastatic factor.
The scientists do have one piece of good news: They found that a drug called rebastinib can interfere with TMEM activity and help overcome chemotherapy’s increased risk of cancer cell metastasis or dissemination.
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