Radioresistance in rectal cancer: can nanoparticles turn the tide?

Abstract

Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.

Keywords: Chemoradiotherapy; Nanomedicines; Radioresistance; Rectal cancer; Treatment.

Fig. 1

Complex genetic landscape between colon and rectal tumors. A Metastasis patterns differences between colon and rectal tumors. B Signaling pathways alterations according to tumor location, C and over the rectum. D Genomic location of APC mutations in tumors arising from the right colon to rectum (upper, middle and lower). *q < 0.05, **q < 0.01, ***q < 0.005, and ****q < 0.001. Reproduced (Adapted) with permission from Chatila et al. [27]. Copyright 2022, Springer Nature. E Correlation between signaling alterations and APC mutation side. *p < 0.05. Reproduced (Adapted) with permission from Mondaca, Walch et al. [28]. Copyright 2020, American Gastroenterological Association Institute F CMS distribution throughout CRC. Reproduced (Adapted) under terms of Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license from Fontana et al. [29]. Copyright 2019, The authors, Published by Oxford University Press on behalf of the European Society for Medical Oncology. APC, Adenomatous polyposis coli; CMS, consensus molecular subtype; CRC, colorectal cancer, PI3K, phosphoinositide 3-kinase; TP53, tumor protein p53

Fig. 2

Schematic representation of the molecular differences between rectal cancer and colon cancer

Fig. 3

Landmark advances in rectal cancer treatment over time

Fig. 4

Tumor cell and cancer-associated fibroblasts crosstalk mediates radioresistance in rectal cancer. A p53 activation in response to radiotherapy-induced DNA damage leads to IGF1 expression and release by CAFs. IGF1-IGFR1 interaction triggers AKT/mTOR signaling, inhibiting the pro-apoptotic factor Bad and fostering cell survival and radioresistance in rectal cancer. B IL-1α release by tumor cells following irradiation triggers an inflammatory CAF polarization and nitrite release. Together, nitrite and radiotherapy-induced DNA damage drive CAFs senescence and cytokines and extracellular matrix constituents release, supporting tumor resistance and progression. IGF1, Insulin-like growth factor 1; CAF, Cancer-associated fibroblast

Fig. 5

miRNA-130a modulates rectal cancer cell response to radiotherapy. High levels of miRNA-130a sensitize rectal tumor cell to radiotherapy by negative regulation on SOX4, downregulating NBS1, involved in DSBs repair, enabling tumor cells to repair radiation-induced DNA damage. DSBs, Double-strand DNA breaks; SOX4, SRY-Box transcription factor 4

Fig. 6

Schematic illustration of different nanomedicine applications in rectal cancer. Nanoparticles harbor intrinsic characteristics capable of radiosensitizing rectal tumors for radiotherapy while acting simultaneously as chemotherapeutic drugs carriers. ATF4, activating transcription factor 4; BVO/ZIS@M, quatrefoil-shaped heterojunction catalyst coated with poly-norepinephrine and macrophage membranes; DMPtNPS, dendritic mesoporous silica nanocarrier with platinum-based nanoparticles; GSH, glutathione; GSSC, oxidized glutathione; eIF2α, eukaryotic initiation factor 2α; ICD, immunogenic cell death; iMOMP, incomplete mitochondrial outer membrane permeabilization; LA, lactic acid; TME, tumor microenvironment; T reg – Regulatory T cell