Evidence for Induction of a Tumor-Metastasis-Receptive Microenvironment in Bone Marrow and Other Organs As an Unwanted and Underestimated Side Effect of Chemotherapy/Radiotherapy

Background. 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. On the other hand, it is very well known that, after infusion into a host after myeloablative treatment by radio-chemotherapy, HSPCs home efficiently to BM in response to several chemotactic factors upregulated in the BM microenvironment.

Hypothesis. To explain this phenomenon, we hypothesized that toxic damage in BM and other organs due to radio and/or chemotherapy administered for treatment of malignancies leads to upregulation in “bystander” tissues of several factors, such as chemokines, growth factors, bioactive phosphosphingolipids, and small- molecule alarmines, that attract normal circulating stem cells for regeneration but unfortunately also provide chemotactic signals to cancer cells that survived the initial treatment.

Materials and Methods. The level of the most important chemotactic factors for cancer cells in organs exposed to radio/chemotherapy, such as stromal-derived factor 1 (SDF-1) and hepatocyte growth factor (HGF), were evaluated by RT-PCR and ELISA. The levels of sphingosine-1-phosphate, ceramide-1-phosphate, and selected alarmines (ATP, UTP) were evaluated by tandem mass spectrometry and/or ELISA. Human rhabdomyosarcoma and ovary cancer cell lines were employed as metastatic models in in vitro and in vivo assays.

Results. We first observed that conditioned media from irradiated BM and other tissues chemoattract human cancer cells. Next, by employing a short in vivo tumor cell tissue-seeding assay we observed that increased numbers of human cancer cells seed (metastasize) to the BM and other organs in SCID/beige immunodeficient mice after irradiation or exposure to chemotherapy. Moreover, we observed that human cancer cells expanded more strongly in the presence of damaged/dying human BM cells, providing evidence that cells expand better on feeder layers of dead cells. Finally, we were able to ameliorate the in vitro migration of cancer cells to CM harvested from irradiated tissues or decrease seeding of in vivo-injected human cells into various organs in irradiated or chemotherapy-exposed mice by inhibiting particular chemoattractant–chemoattractant receptor axes (e.g., SDF-1–CXCR4 or S1P–S1P₁R), and a very efficient protective effect was observed by reducing the pro-inflammatory response induced by radio/chemotherapy by administering non-steroid anti-inflammatory drugs or dexamethasone in vivo in experimental animals.

Conclusions. We propose that a radio-chemotherapy-induced pro-metastatic microenvironment plays an important role in the metastasis of cancer cells to bones as well as other organs (lungs or liver), which are highly susceptible to chemotherapeutic agents or 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 that are resistant to treatment. Such cells possess characteristics of cancer stem cells and are highly migratory. Since many different chemoattractant-specific receptor axes are involved in this phenomenon, simple, intensive anti-inflammatory treatment by non-steroid agents to suppress induction of pro-metastatic factorsafter radio/chemotherapy seems to be an interesting alternative.