Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy

Abstract

There are well-known side effects of chemotherapy and radiotherapy that are mainly related to the toxicity and impaired function of vital organs; however, the induction by these therapies of expression of several pro-metastatic factors in various tissues and organs that in toto create a pro-metastatic microenvironment is still, surprisingly, not widely acknowledged. In this review, we support the novel concept that toxic damage in various organs leads to upregulation in “bystander” tissues of several factors such as chemokines, growth factors, alarmines, and bioactive phosphosphingolipids, which attract circulating normal stem cells for regeneration but unfortunately also provide chemotactic signals to cancer cells that survived the initial treatment. We propose that this mechanism plays an important role in the metastasis of cancer cells to organs such as bones, lungs, and liver, which are highly susceptible to chemotherapeutic agents as well as ionizing irradiation. This problem indicates the need to develop efficient anti-metastatic drugs that will work in combination with, or follow, standard therapies in order to prevent the possibility of therapy-induced spread of tumor cells.

Bioactive Lipids, LPC and LPA, Are Novel Prometastatic Factors and Their Tissue Levels Increase in Response to Radio/Chemotherapy

“…Moreover, we observed that both S1P and C1P are upregulated in BM tissues after radio/chemotherapy, which supports the concept that one of the unwanted effects of radio/chemotherapy is induction of a pro-metastatic microenvironment in normal tissues damaged by treatment (11) and that factors induced by such treatment may be involved in metastasis of cancer cells resistant to the treatment (11, 12). Based on this concept, we became interested in two other bioactive lipids, namely, lysophosphatidylcholine (LPC) and its derivative generated by enzymatic action of autotaxin (ATX), lysophosphatidic acid (LPA) (13, 14).…”

“…We have proposed that one of the unwanted side effects of radio/chemotherapy is induction of a pro-metastatic environment in different tissues (11, 12). To see whether radio/chemotherapy could increase LPA and LPC levels in organs affected by systemic treatment, LPA and LPC levels were measured in supernatants harvested from murine BM, liver, lungs, and brain, which are frequent sites of RMS metastasis before or after exposure to irradiation or VCR administration, by employing a sensitive mass spectrometry-based approach.…”

Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics

“…Evaluation of therapyinduced changes of the CAFs should be carefully quantified using automated image analysis and statistically evaluated through multivariate analysis [110]. Chemotherapeutics activate CAFs to create a chemoresistant niche by the release of cytokines including interleukins and TGF-β [51,65,83]. Intriguingly, combinational treatment of nab-paclitaxel (Abraxane) and gemcitabine normalizes the amount of CAFs compared to gemcitabine alone in patients with pancreatic cancer [2].…”

Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression

“…For treatment of more advanced or recurrent cervical cancer, several chemotherapy drugs such as cisplatin, paclitaxel, ifosfamide and 5-fluorouracil (5-Fu) have been used (Nguyen and Nordqvist 1999;Tanaka et al 2006;Zanetta et al 2000). However, there are several side effects of these therapies (Ratajczak et al 2013). Thus, reducing the side effects of chemotherapy by using a natural product could be applicable (Cheah et al 2014;George and Henkel 2014;Yu et al 2013).…”