Transfer of malignant trait to immortalized human cells following exposure to human cancer serum

Abstract

Background: Human cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation. This process might contribute to tumor progression and invasion through delivery of oncogenes or inhibitors of tumor suppressor genes, derived from the primary tumor cells, to susceptible target cells. The oncogenic potential of human cancer serum has been described in immortalized mouse fibroblasts but has not been shown yet in human cells. The objective of this study was to determine whether metastatic cancer patient sera have the ability to induce neoplastic transformation in immortalized human embryonic kidney (HEK293) cells, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs) and human adult liver fibroblasts (hALFs). Methods: Early passage HEK293 cells, hESCs, hMSCs and hALFs were exposed to cancer patient serum, or cancer cells-derived condition medium for 3 weeks. Treated cells were analyzed for cell proliferation and transformation both in vitro and in vivo. Results: HEK293 cells exposed to cancer serum increased their proliferative capability and displayed characteristics of transformed cells, as evaluated by in vitro anchorage-independent growth assay and in vivo tumorigenesis in immunodeficient mice. The same phenotypes were acquired when these cells were cultured in cancer cell line conditioned medium suggesting that the putative oncogenic factors present in the serum might derive directly from the primary tumor. Histopathological analyses revealed that the tumors arising from cancer patient serum and conditioned medium-treated HEK293 cells were poorly differentiated and displayed a high proliferative index. In contrast, neither of these phenomena was observed in treated hMSCs and hALFs. Intriguingly enough, hESC-treated cells maintained their self-renewal and differentiation potentials, as shown by in vitro sphere formation assay and in vivo development of teratomas in immunodeficient mice. Conclusion: Our results indicate that cancer patients serum is able to induce oncogenic transformation of HEK293 cells and maintain the self-renewal of hESCs. To our knowledge, this is the first study that demonstrates the oncogenic transformation potential of cancer patient serum on human cells. In depth characterization of this process and the molecular pathways involved are needed to confirm its validity and determine its potential use in cancer therapy.

Liquid biopsy by NGS: differential presence of exons (DPE) in cell‐free DNA reveals different patterns in metastatic and nonmetastatic colorectal cancer

“…Differential detection of exons suggests differential release of cfDNA, supporting the idea of an active release of nucleic acids by cells, perhaps as a means of intercellular communication. Horizontal transfer of DNA between cells has been proposed as a pivotal mechanism in the development of metastasis both in vitro and in vivo, a phenomenon called genometastasis [36][37][38][39]. Consistent with this, several publications support the idea that various cell types selectively release newly synthesized DNA, probably associated with lipid and protein complexes, as an aspect of homeostatic processes [40,41].…”

Oncogenic Regulation of Extracellular Vesicle Proteome and Heterogeneity

“…In several such instances, recipient cells adopted phenotypic traits dictated by the oncogenic cargo, such as changes in cell shape, activation of downstream signaling pathways, altered responses to extracellular cues, pro‐angiogenic activity, and other properties . In some cases the EV‐mediated interactions between cancer and non‐transformed cells led to states resembling malignant transformation, especially following transfer of EV‐associated genomic DNA or RNA . However, other studies argue that horizontal transformation is transient or takes place due to secondary (possibly epigenetic) events and permanent changes due to oncogene transfer to recipient normal cells are unlikely .…”

Novel blood test to predict neoplastic activity in healthy patients and metastatic recurrence after primary tumor resection

“…The above effect was not seen if these cells were exposed to sera coming from healthy patients. 25,26 Cells transformed even when they were exposed to conditioned media obtained from colon cancer cell cultures proving that the oncotransforming factors were actually produced by cancer cells. Based on these observations, we hypothesize that the ability of SOM cells to incorporate cancer factors could constitute the basis of a novel in vitro serum-based platform that could function both as a cancer screening test for healthy patients and as a predictor of metastatic recurrence after primary tumor resection in cancer patients.…”