Multiscale modelling of cancer progression and treatment control : the role of intracellular heterogeneities in chemotherapy treatment

Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.PostprintPeer reviewe

Targeting the tumor microenvironment in colorectal peritoneal metastases

Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma

Growth of confined cancer spheroids: a combined experimental and mathematical modelling approach

We have integrated a bioengineered three-dimensional platform by generating multicellular cancer spheroids in a controlled microenvironment with a mathematical model to investigate\ud confined tumour growth and to model its impact on cellular processes

miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

Immune targets in the tumor microenvironment treated by radiotherapy.

Radiotherapy (RT), the major anti-cancer modality for more than half of cancer patients after diagnosis, has the advantage of local tumor control with relatively less systematic side effects comparing to chemotherapy. However, the efficacy of RT is limited by acquired tumor resistance leading to the risks of relapse and metastasis. To further enhance the efficacy of RT, with the renaissances of targeted immunotherapy (TIT), increasing interests are raised on RT combined with TIT including cancer vaccines, T-cell therapy, and antibody-based immune checkpoint blockers (ICB) such as anti-CTLA-4 and anti-PD1/PD-L1. In achieving a significant synergy between RT and TIT, the dynamics of radiation-induced response in tumor cells and stromal cells, especially the cross-talk between tumor cells and immune cells in the irradiated tumor microenvironment (ITME) as highlighted in recent literature are to be elucidated. The abscopal effect refereeing the RT-induced priming function outside of ITME could be compromised by the immune-suppressive factors such as CD47 and PD-L1 on tumor cells and Treg induced or enhanced in the ITME. Cell surface receptors temporally or permanently induced and bioactive elements released from dead cells could serve antigenic source (radiation-associated antigenic proteins, RAAPs) to the host and have functions in immune regulation on the tumor. This review is attempted to summarize a cluster of factors that are inducible by radiation and targetable by antibodies, or have potential to be immune regulators to synergize tumor control with RT. Further characterization of immune regulators in ITME will deepen our understanding of the interplay among immune regulators in ITME and discover new effective targets for the combined modality with RT and TIT