Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation

Abstract

Cisplatin-based chemotherapeutic regimens are the most frequently used (neo)adjuvant treatments for the majority of solid tumors. While platinum-based chemotherapeutic regimens have proven effective against highly proliferative malignant tumors, significant relapse and progression rates as well as decreased overall survival are still observed. Currently, it is known that sub-populations of chemoresistant cells share biological properties with cancer stem cells (CSC), which are believed to be responsible for tumor relapse, invasion and ultimately disease dissemination through acquisition of mesenchymal cell traits. In spite of concentrated efforts devoted to decipher the mechanisms underlying CSC chemoresistance and to design targeted therapeutics to these cells, proteomics has failed to unveil molecular signatures capable of distinguishing between malignant and non-malignant stem cells. This has hampered substantial developments in this complex field. Envisaging a novel rationale for an effective therapy, the current review summarizes the main cellular and molecular mechanisms underlying cisplatin resistance and the impact of chemotherapy challenge in CSC selection and clinical outcome. It further emphasizes the growing amount of data supporting a role for protein glycosylation in drug resistance. The dynamic and context-dependent nature of protein glycosylation is also comprehensively discussed, hence highlighting its potentially important role as a biomarker of CSC. As the paradigm of cancer therapeutics shifts towards precision medicine and patient-tailored therapeutics, we bring into focus the need to introduce glycomics and glycoproteomics in holistic pan-omics models, in order to integrate diverse, multimodal and clinically relevant information towards more effective cancer therapeutics.

The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer

“…This includes patients with either hematological or solid cancers, and low expression of CD47 on tumor cells was in many cases associated with a better prognosis and an improved survival of patients . It is known that cancer development and metastasis formation are primarily driven by so‐called tumor‐initiating cells and/or cancer stem cells (CSC), populations of cancer cells with strong capacity for self‐renewal, which are often also more resistant to many conventional cancer therapies . Of interest, CSC self‐renewal appears to be regulated by CD47‐TSP‐1 interactions [reviewed in ].…”

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

“…Platinum (Pt)‐based chemotherapies are frequently used as an adjuvant for ovarian cancer treatment . However, drug resistance is still a major obstacle that limits efficacy of Pt‐based therapeutic regimens . Since the 1970s, tolerance to Pt has been blamed on effects unrelated to DNA damage.…”

The bad seed: Cancer stem cells in tumor development and resistance

“…Regardless of the origin, drug resistance in cancer as well as of CSCs to current therapeutics is a well-known phenomenon, providing an explanation as to why conventional therapies are often ineffective at eradicating cancer cells (Colak and Medema, 2014;Ferreira et al, 2016;Gonen and Assaraf, 2012;Livney and Assaraf, 2013;Niewerth et al, 2015;Zhitomirsky and Assaraf, 2016). Hence, given the remarkable regenerative capacity of CSCs, our future vision of cancer therapy must aim, not simply to reduce tumor mass, but to extinguish the burning flame of the tumor.…”