CRIPTO Is a Marker of Chemotherapy-Induced Stem Cell Expansion in Non-Small Cell Lung Cancer

Abstract

Chemotherapy is the mainstay for the treatment of non-small cell lung cancer (NSCLC). However, NSCLC cells are either intrinsically chemoresistant or rapidly develop therapy resistance. Cancer stem cells (CSCs) are widely recognized as the cell population responsible for resistance to systemic therapies, but the molecular responses of CSCs to chemotherapeutic agents are largely unknown. We identified the embryonic protein CRIPTO in stem cell-enriched spheroid cultures of adenocarcinoma (AC) and squamous cell carcinoma (SCC) derived from NSCLC surgical specimens. The CRIPTO-positive population had increased clonogenic capacity and expression of stem cell-related factors. Stemness-related properties were also obtained with forced CRIPTO expression, whereas CRIPTO downregulation resulted in cell cycle blockade and CSCs death. Cell populations positive and negative for CRIPTO expression were interconvertible, and interfering with their reciprocal equilibrium resulted in altered homeostasis of cell expansion both in spheroid cultures and in tumor xenografts. Chemotherapy treatment of NSCLC cells resulted in reduction of cell number followed by increased CRIPTO expression and selective survival of CRIPTO-positive cells. In NSCLC tumor xenografts, chemotherapeutic agents induced partial cell death and tumor stabilization followed by CRIPTO overexpression and tumor progression. Altogether, these findings indicate CRIPTO as a marker of lung CSCs possibly implicated in cancer cell plasticity and post-chemotherapy tumor progression.

Analysis of Dormancy-Associated Transcriptional Networks Reveals a Shared Quiescence Signature in Lung and Colorectal Cancer

“…NSCLC and CRC specimens were obtained from patients undergoing surgical resection and used to generate multicellular spheroid cultures that were validated by genomic and proteomic analyses, marker expression and ability to reproduce phenocopies of the parental tumors when inoculated in immunocompromised mice [ 3 , 22 , 24 , 25 , 26 ]. NSCLC and CRC spheroids were stained with the lipophilic membrane dye PKH26, which is rapidly lost by actively proliferating cells and retained by slowly proliferating/quiescent cells.…”

Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

“…By contrast, low-dose chemotherapy achieved tumor stabilization without inducing CAF pro-tumorigenic signalling, thus enhancing treatment response and the survival of mice carrying breast and pancreatic tumor xenografts [140]. Additional support to this model has been recently provided by the observation that in lung cancer primary cells and xenografts, chemotherapy induced the expression of the stem cell marker CRIPTO resulting in aggressive tumor cell expansion [141]. In line with this observation, an accelerated tumor regrowth has been reported in lung cancer patients upon chemotherapy treatment [142,143].…”