Mini-reviewTumor microenvironment and cancer therapy resistance
Introduction
The steps of tumor development implicate co-evolution of malignant cells and benign constituents of the surrounding stroma, while dynamic interactions between pathologically altered parenchyma and stroma within the TME represents a critical paradigm now considered among the typical hallmarks of cancer [1]. Histologically the association of infiltrating leukocytes and tumorigenesis was first described by Rudolf Virchow in 1863 to propose the potential relevance of chronic inflammation to neoplastic events [2]. Subsequently in 1889, Stephen Paget contributed a “seed and soil” concept to delineate the distinct patterns of recurrent metastatic sites in human breast cancer, and to plausibly interpret the tropism of tumor metastases to specific organs [3]. To date, a plethora of studies have disclosed the unique aspects of the TME, with its mystical veil removed and diverse characteristics ascertained. It is increasingly evident that individual compartments of the TME do not stay as quiet bystanders, but significantly regulate tumor initiation, disease progression, metastatic development, and more importantly, therapeutic response. Among multiple TME-implicated activities, clinical response to therapies is the major factor that directly determines the long term fate of patients who undergo anticancer interventions. In this review, an updated picture of tumor–stroma interaction is depicted, with a particular emphasis on the capacity of the TME in modifying cancer sensitivity to therapeutic agents. An appropriate, thorough and in-depth understanding of the functional roles of TME in disease evolution is essential for rational design, reasonable innovation and successful translation of novel anticancer approaches to precise medicine with substantially improved clinical outcomes.
Section snippets
The TME orchestrates disease progression and dominates therapeutic responses
As a most lethal age-related pathology that imperils human health, cancer progresses with the surrounding TME to achieve continuous outgrowth and ensuing metastasis that correlates with the majority of cancer-related death [4]. Despite considerable advancements in therapeutic concepts and techniques, disease relapse with limited response remains a major challenge and confers poor prognosis in clinical oncology. Cancer resistance involves intrinsic mechanisms that are determined by pre-existing
Damage responses of the TME offset therapy-enforced tumor regression
First introduced into clinics in 1940s for preliminary uses of nitrogen mustards and antifolate drugs, chemotherapy constitutes the mainstay of modern anticancer regimes and demonstrated remarkable potency in controlling malignancies including leukemia, lymphoma and most solid tumors [64]. However, the technical limitations of chemotherapy discovered by the early researchers still remain, and the major downside has been the low efficiency in distinguishing between normal and cancer cells.
Implications of personalized cancer therapy in an era of precision medicine
Personalized cancer therapy (PCT) takes advantage of informative clues from the tumor and its microenvironment, together with distinct conditions of the patient, to tailor therapeutic regimes and treat the disease more effectively with less toxicity. PCT delivers a similar concept with “individualized cancer therapy” (ICT) that aims to design strategies for a person diagnosed with cancer, through covering drug sensitivity testing, cancer biomarkers and bioinformatics detection,
Concluding remarks and future avenues
Next generation sequencing (NGS) enables genome-wide personalized oncology efforts with the specialty and infrastructure necessary for identification and prioritization of tumor genome variants, as piloted by the oncomine comprehensive panel (OCP) which represents a streamlined and broadly applicable targeted NGS system to advance precision oncology [102]. In contrast, biological mechanisms of resistance to conventional cytotoxic chemotherapeutics and targeted therapies designed for specific
Conflict of interest
There is no conflict of interest regarding the publication of this paper.
Acknowledgements
The author sincerely apologizes for not being able to thoroughly cite the contribution of all studies related to the current topic due to space restriction, and gratefully acknowledges Drs. Peter Nelson, Judith Campisi, Stephen Plymate and their lab members for inspiring discussion and insightful comments that made the manuscript possible. This work was supported by grants from the U.S. Department of Defense (DoD) Prostate Cancer Research Program (PCRP) (Idea Development Award PC111703),
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