Metabolism, Metastasis and Drug Resistance in Cancer

Jiawei Liu

999 Xuefu Avenue, Honggutan District, Nanchang City, Jiangxi Province, China

Keywords:

Cancer, Metabolism, Metastasis, Drug Resistance.

Abstract:

Cancer is a heterogeneous disease caused by abnormal cell mutation, which has the characteristics of

continuous growth, invasion and metastasis. Despite research advances in cell biology, physiology and

pharmacology over the past decades, the mortality of cancer remains a healthcare issue. Current treatments

are not very effective in treating advanced tumors. Tumor microenvironment (TME) is a complex

environment referring to the surrounding tumor cells, including surrounding blood vessels, immune cells,

fibroblasts, bone marrow-derived inflammatory cells, various signal molecules and extracellular matrix

(ECM). A large number of studies have proved the key role of tumor microenvironment in the development

of cancer. Cancer associated fibroblasts (CAFs) interact with cancer cells to produce growth factors,

inflammatory factors and other factors, inhibit the immune system and promote tumor proliferation and

invasion. Tumor cells provide good conditions for cancer development by remodeling ECM and glycolysis.

This paper has aims and objectives to outline the effects of the interaction between TME and tumor cells on

tumor metabolism, metastasis and drug resistance. The molecular mechanism of TME change promoting

tumor development is discussed and the current therapeutic strategies for targeting tumor drug resistance are

mentioned. Future research with the help of artificial intelligence using large data sets as well as genome

sequencing from cancer patients is required to identify novel targets with fewer side effects in different

individuals for personalized medicine.

1 INTRODUCTION

Cancer is the second leading cause of death in the

world. While medical advancements over the past

few decades have increased the survival rate of

cancer, still cancers mortality rate remains. The

World Health Organization International Agency for

research on cancer (IARC) estimated that there were

19.29 million new cancer cases in 2020, including

10.06 million males and 9.23 million females,

causing 9.96 million cancer deaths worldwide,

including 5.53 million males and 4.43 million

females. Although research advances have tackled

some diseases such as infections successfully, cancer

still has a high mortality. While both tumor and

normal tissues are composed of various cell types, the

physiological functions of tumor and normal organs

are different (Egeblad, Nakasone et al. 2010).

One of the most common phenotypes of cancer

cells is uncontrolled cell proliferation. Despite

understanding the mechanism of the cell cycle, many

https://orcid.org/0000-0003-3524-3355

treatments are not specific and have severe side

effects with negative consequences on healthy and

rapidly dividing cell. The rapid growth of cancer cells

is mainly due to mutations conferring the ability to

use a wide range of nutrients to adapt to changing

environmental conditions. Current genome

engineering methods such as CRISPR/Cas gene

editing is not specific and validated for use in cancer

(Hanahan, Weinberg 2011). For example, tumor cells

are mainly powered by aerobic glycolysis rather than

glucose oxidative phosphorylation in their

microenvironment, and an increased expression of

fatty acid synthase (FASN) causes elevated fatty acid

synthesis during tumorigenesis of breast and prostate

cancers to support tumor metabolism, maintenance

and growth, or competitively damage anti-tumor

immunity (Lyssiotis, Kimmelman 2017).

While there are plenty of information about

metabolism, metastasis and drug resistance in cancer,

still significant unknown areas are present in our

knowledge. This paper aims to provide a brief

878

Liu, J.

Metabolism, Metastasis and Drug Resistance in Cancer.

DOI: 10.5220/0011311900003443

In Proceedings of the 4th Inter national Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 878-882

ISBN: 978-989-758-595-1

overview of the existing information, point out to

gaps in our knowledge and propose some ideas for

future research, hoping to provide a summary for

clinicians and researchers working on cancer as well

as opening new avenues for research and discussion.

2 METHODS AND MATERIALS

2.1 Aims and Objectives

This paper aims to investigate existing published and

peer-reviewed literature on metabolism, metastasis

and drug resistance in cancer to identify gaps in our

knowledge about the topic.

2.2 Designed Approach for the

Literature Search

A search strategy was designed and followed to

identify appropriate peer-reviewed articles written in

English from 2005-2020 from the publicly available

database PubMed.

The following terminology was used to identify

papers: cancer AND metastasis AND metabolism

AND drug resistance in the search engine.

2.3 Inclusion and Exclusion Criteria

Papers published in languages other than English and

beyond the date bracket of 2005-2020 were excluded

from the final search result.

3 DISCUSSION

Studying metabolic changes of cancer cells, including

epigenetic processes that may lead to tumorigenesis,

malignancy and cancer stem cell generation can help

us to find more effective treatments. While surgical

resection can treat some tumors during the early

stages of tumorigenesis, metastasis can lead to tumor

recurrence and even death (Steeg 2016). Therefore,

controlling the metastasis of cancer cells is one of the

crucial means to reduce mortality among cancer

patients. The stability of the normal epithelium

structure acts as the internal barrier against the

invasion of cancer cells. Epithelial mesenchymal

transition (EMT) is the key to metastasis and invasion

that is usually defined by the loss of epithelial marker

E-cadherin and the increase of mesenchymal marker

vimentin (Liu, Liu et al. 2018). The initial metastatic

cells usually undergo EMT (Thiery, Acloque et al.

2009), change their shape, transform their

metabolism, enter lymphatic vessels or vascular

lumens ， attach to other cells as well as the

extracellular matrix to invade and transfer to other

parts of the body through venous and arterial

circulation (Pantel, Brakenhoff et al. 2008) (Figure

1).

Figure 1：An overview of different stages of cancer metastasis cascade from invasion to colonization. The figure was

generated using Biorender.

Besides surgery, radiotherapy, immunotherapy,

endocrine therapy and gene therapy have been used

in the treatment of various cancers. Chemotherapy is

still a common method in the treatment of cancer

(Figure 2) due to many factors, such as its potential to

destroy cancer cells and ease of administration in the

treatment of inoperable cancer.

Metabolism, Metastasis and Drug Resistance in Cancer

879

Figure 2: Basic methods of chemotherapy, including different drugs and chemicals used on different components of cancer

cells and their function. The figure was generated using Biorender.

Beyond issues such as side effects to damage

healthy cells, drug resistance can hinder

chemotherapy. Drug resistance can emerge because

of tumor heterogeneity, tumor growth kinetics,

undruggable genomic drivers, selective therapeutic

pressure such as the abnormal expression of drug

transporters as efflux transporters increased and

uptake transporters decreased, immune system and

tumor microenvironment, as well as the presence of

gene mutation (loss of tumor suppressor genes,

abnormal expression of proto-oncogenes) (Luqmani

2005) (Figure 3).

Figure 3. The determinants of cancer drug resistance and several ways to overcome drug resistance. The figure was generated

using Biorender.

3.1 Tumor Microenvironment, Tumor

Growth, and Metastasis

The environment within the tissue strongly affects the

survival and proliferation of tumor cells. Tumor cells

transform their environment to form tumor

microenvironment (TME) to maintain their survival

and proliferation (Reina-Campos, Moscat et al.

2017). Understanding the effect of cellular and non-

cellular components in TME on the metabolism of

cancer cells can provide a new way for the diagnosis

and treatment of cancer. Under normal

circumstances, the main function of activated

fibroblasts is tissue regeneration (Du, Che 2014).

During carcinogenesis, cancer cells produce a loose

microenvironment which is conducive to the further

development and invasion of tumor. The

microenvironment changes its own morphological

characteristics, which not only leads to an increase of

the number of immune and inflammatory cells such

as macrophages, but more importantly, mediates

recruitment of cancer related fibroblasts (CAFs) into

the tumor matrix by the growth factors secreted by

tumor cells. CAF supports the growth, movement and

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

880

invasion of cancer cells, leading to tumor progression,

metastasis and chemoresistance(Du, Che 2014).

CAF acts similar to pro-inflammatory factors in

the early stage of cancer development. Inflammatory

immune cells accumulate in the inflammation sites to

provide soluble growth and survival factors, matrix

remolding enzymes, reactive oxygen species and

other bioactive molecules(Kuzet and Gaggioli 2016).

These components have different effects on the

proliferation, angiogenesis, invasion and metastasis

of cancer cells.

The immune system can prevent the occurrence of

primary tumor (through immune surveillance) and

metastasis by recognizing tumor specific antigen

(Bai, Meng et al. 2019). However, tumor can induce

anti-tumor immune response and immune

suppression mechanism to avoid the attack of

immune system. Macrophages are two phenotypes:

M1 like macrophages and M2 like macrophages. The

development of cancer is closely related to the

transformation of macrophages (Bai, Meng et al.

2019). The differentiation, growth and chemotaxis of

macrophages are regulated by a variety of growth

factors. colony-stimulating factor-1 (CSF-1) induces

macrophages to transform into highly plastic non

polarized (M0) macrophages. NF-κB in TME and p50

form dimer to inhibit NF-κB signal promotes

macrophages to transform from M1 inflammatory

phenotype to M2 trophic phenotype (Bai, Meng et al.

2019). This change will promote the development of

malignant tumors (Figure 4).

Figure 4: The role of different immune cells in the proliferation of tumor cells. The figure was generated using Biorender.

4 CONCLUSION AND OUTLOOK

Complex TME supports the growth, metastasis and

drug resistance of primary tumors. Studying the

mechanism of TME affecting tumor development

may facilitate cancer diagnosis and provides more

effective treatments. Determining the development

stage of tumor by identifying tumor markers can

improve the prognosis of patients. However, the

detection of a single biomarker often cannot

accurately explain the problem. Therefore, the current

research direction is to detect multiple biomarkers to

more accurately judge the development process of

cancer and predict the prognosis of patients. The

detection of some biomarkers for TME mentioned in

this paper provides new approaches for cancer

diagnosis, monitoring and treatment development. At

the same time, it provides guidance for doctors to

formulate appropriate treatment methods. The study

of the mechanism of tumor reprogramming

microenvironment and the development of drugs for

TME has created a new era of cancer medicine. At

present, some targeted therapies have been

developed. Compared with traditional chemotherapy

and radiotherapy, it has better therapeutic effects and

fewer side effects, which brings hope to develop new

treatment methods for cancer that are difficult to treat

by conventional means. Future research with the help

of artificial intelligence utilizing big data sets is

required to establish a robust map of key molecules

in tumor microenvironment for each cancer.

Furthermore, potential molecules identified from

such ‘connectome’ of tumor microenvironment can

be tested for drug responsiveness to design more

effective medication targets with fewer side effects.

In addition, with the availability of genome testing,

Metabolism, Metastasis and Drug Resistance in Cancer

881

tumors genome in different individuals can be

genetically sequenced to identify specific mutations

and provide them with specific treatment for

personalized medicine.

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