Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment

Abstract

Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)—a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/β-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a ‘silver-bullet’ single-target approach.

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

“…As amply argued elsewhere, many in the oncology community believe that adding one or two drugs will not potently inhibit a currently deadly metastatic tumor like rhabdomyosarcoma [154][155][156][157][158]. We can not expect any one or two drugs added to current cytotoxic chemotherapies to have strong disease inhibiting effects.…”

“…We therefore turn to multidrug combination cancer treatments to achieve fractional cell killing or fractional growth inhibition through drug additivity, as in Palmer et al [156]. And as in Kilmister et al "...effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways...in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach" [158]. And as Lindsey et al say specifically for osteosarcoma, it "continues rapidly modifying its genotype, thus making potential targeted molecular therapeutics increasingly impractical" [159].…”

Spatial Transcriptomics: A Powerful Tool in Disease Understanding and Drug Discovery

“…This capability substantially enhances our understanding of cellular interactions and spatial impacts within the TME. Metastasis is a crucial factor contributing to high cancer mortality rates and is closely associated with drug resistance 74 . Therefore, identifying key genes and pathways involved in metastasis may reveal potential therapeutic targets for cancer treatment.…”

Transcriptomic Maps of Colorectal Liver Metastasis: Machine Learning of Gene Activation Patterns and Epigenetic Trajectories in Support of Precision Medicine

“…These CSCs constitute presumably a small population of highly tumorigenic cells, possessing pluripotency and self-renewal properties that drive metastasis and treatment resistance. This process is sustained by a dynamic TME [107]. Complex interactions between the TME and CSC not only maintain stemness but also fuels tumor evolution into aggressive, invasive, migratory phenotypes [100], a process thought to be under the influence of epigenetic control [108].…”