Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Abstract

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review)

“…The abnormal expression of NF-κB has also been detected in CRC cells ( 122 ). In an experiment involving the intraperitoneal injection of mutant IκB colon cells into mice suffering from metastatic CRC, it was discovered that this approach improved the survival rate of the mice, suggesting that NF-κB inhibition mediates the cell-killing effect caused by TRAIL ( 123 ). Similarly, NEDD8 is abnormally activated in CRC tissues.…”

“…It can be inferred that NEDD8's presence in CRC inhibits IκB from activating the NF-κB pathway, thereby inhibiting TRAIL-mediated cell killing and allowing cancer cells to survive in the face of chemical drugs. In light of the deleterious ramifications stemming from cancer cells' resistance to platinum-based drugs, notably oxaliplatin, in the majority of CRCs ( 123 ), the targeted development of pharmaceutical agents along this pathway holds immense promise. This endeavor has the potential to furnish novel therapeutic strategies for treatment-resistant CRC ( Fig.…”

Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling

“…Meanwhile, CAF activity is also regulated by proinflammatory factors such as interleukin-1β (IL-1β) and transforming growth factor β (TGFβ). It has been indicated that IL-1β and TGFβ could recruit CAF to the TME ( Guillén Díaz-Maroto et al, 2019 ), which subsequently induces the carcinogenesis pathways within CRC cells, including JAK/STAT, PI3K/Akt, and activates hedgehog transcription factor GLI2, leading to cancer stem cells (CSCs) proliferation and intrinsic chemotherapy resistance ( Tang et al, 2018 ; Guillén Díaz-Maroto et al, 2019 ; Linares et al, 2023 ). In addition, CAF could secrete a variety of tumor-nourishing cytokines.…”

Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer

“…The response to treatment is highly variable and not durable in the majority of cases. This dismal clinical perspective is impacted by various factors, including tissue tropism effects that allele-specific RAS mutants have in combination with other actionable alterations 6 , clonal heterogeneity 7 , phenotypic plasticity 8 , location of tumor 9 , and the tumor microenvironment 10 . Collectively, these findings highlight the need for novel therapies focused specifically on the personalized treatment of CRC.…”