טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBerkovich Hila
SubjectThe Pro-Tumorigenic Role of Platelets Following Chemotherapy
DepartmentDepartment of Medicine
Supervisors Professor Peleg Hasson
Professor Yuval Shaked
Full Thesis textFull thesis text - English Version


Abstract

Chemotherapy is one of the most common treatment modalities for cancer. We have previously shown that certain chemotherapy drugs, in addition to their anti-tumor activity, may also induce pro-tumorigenic and pro-metastatic unwanted effects that are contributing to tumor relapse. We found that these pro-tumorigenic effects are generated by the host in response to the therapy. Since platelets have been recently shown to facilitate delivery of angiogenesis, inflammatory regulators and growth factors to pathological sites, including to tumors, we asked whether platelets are a major component conveying the host pro-tumorigenic effects in response to therapy, and whether they act so by increased uptake of pro-tumorigenic factors from the circulation, releasing them at the treated tumor site or at pre-metastatic sites. Our results show that tumor bearing mice treated with paclitaxel (PTX) or Folfox (oxaliplatin, folinic acid and 5-fluorouracil) chemotherapies, exhibited increased number of platelets in the treated tumors compared to tumors from untreated mice. In addition, a substantial increase in invasion properties of tumor cells was observed in the presence of platelet lysate or platelet rich plasma (PRP) from non-tumor bearing mice treated with PTX or Folfox when compared to poor platelet plasma (PPP) or platelet depleted PRP obtained from the same mice. Moreover, platelets' conditioned-medium derived from Folfox treated mice induced an elevation in MMP9 expression, and tumor cells cultured with platelets from PTX or Folfox treated mice underwent epithelial to mesenchymal transition (EMT), both are characteristic of metastatic state of cancer cells. PRP obtained from mice after treatment with PTX or Folfox induced human umbilical vein endothelial cells (HUVECs) tube formation, demonstrating local angiogenesis, in contrast to plasma obtained from platelet-depleted mice prior to the same treatments. We found that systemic angiogenesis facilitated by bone marrow derived cells (BMDCs) mobilization such as circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) was blocked in platelet-depleted mice compared with the control mice following chemotherapy. In-vivo and ex-vivo evaluation of tumor cell seeding using tail vein injection - experimental lung metastasis assay, and pulmonary metastasis assay (PuMA), respectively, revealed increased metastatic lesions in lungs of Folfox or PTX treated-mice.  However, this effect was not observed in mice depleted from platelets.  Overall, our results indicate that the host response to chemotherapy, which enhances tumor aggressiveness, is mediated in part by platelets, and that it can be blocked by platelets depletion, suggesting that the host response manifestations are platelets-mediated.