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Connecting the mechanisms of tumor sex differences with cancer therapy

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Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Sex differences in cancer incidence and survival are constant and pronounced globally, across all races and all age groups of cancer types. In 2016, after the National Institutes of Health proposed a policy of utilizing sex as a biological variable, researchers started paying more attention to the molecular mechanisms behind gender variations in cancer. Historically, most previous studies investigating sex differences have been centered on gonadal sex hormones. Nevertheless, sex differences also involve genetic and molecular pathways that run throughout the entire process of cancer cell proliferation, metastasis, and treatment response, in addition to sex hormones. In particular, there is significant gender dimorphism in the efficacy and toxicity of oncology treatments, including conventional radiotherapy and chemotherapy, as well as the emerging targeted therapies and immunotherapy. To be clear, not all mechanisms will exhibit gender bias, and not all gender bias will affect cancer risk. Our goal in this review is to discuss some of the significant sex-related changes in fundamental cancer pathways. To this purpose, we summarize the differential impact of gender on cancer development in three dimensions: sex hormones, genetics, and epigenetics, and focus on current hot subjects including tumor suppressor function, immunology, stem cell renewal, and non-coding RNAs. Clarifying the essential mechanisms of gender differences will help guide the clinical treatment of both sexes in tumor radiation and chemotherapy, medication therapy with various targets, immunotherapy, and even drug development. We anticipate that sex-differentiated research will help advance sex-based cancer personalized medicine models and encourage future basic scientific and clinical research to take sex into account.

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Data availability

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Abbreviations

HCC:

Hepatocellular carcinoma

SNV:

Single nucleotide variant

CNA:

Copy number alteration

DMGs:

Differentially methylated genes

IGF-2:

Insulin growth factor-2

CSCs:

Cancer stem cells

HSCs:

Hematopoietic stem cells

HSCT:

Hematopoietic stem cell transplantation

MM:

Multiple myeloma

E2:

Estradiol

IL:

Interleukin

UPR:

Unfolded protein response

ER:

Estrogen receptor

AR:

Androgen receptor

TLR:

Toll-like receptor

AID:

Acquired immunodeficiency disease

MAMPs:

Microbial associated molecular patterns

DCs:

Dendritic cells

APCs:

Antigen-presenting cells

B7-H1:

B7-homologue 1

mTOR:

Mammalian target of rapamycin

Treg:

T regulatory cell

NK:

Natural killer

CTL:

Cytotoxic T lymphocyte

ADT:

Androgen deprivation therapy

TMZ:

Temozolomide

miRs:

MicroRNAs

XIAP:

X-linked inhibitor of apoptosis protein

lncRNA:

Long non-coding RNA

ESRRG:

Estrogen related receptor gamma

XCI:

X chromosome inactivation

XIC:

X inactivation centre

EXITs:

Escape from X-inactivation tumour suppressors

PAR:

Pseudoautosomal region

BCa:

Bladder cancer

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

NSCLC:

Non-small cell lung carcinoma

ALT:

Alternative lengthening of telomere

NEM:

Non-expression mutation

TSGs:

Tumor suppressor genes

NTDs:

Neural tube defects

G6PD:

Glucose-6-phosphate dehydrogenase

HLA-C:

Human leukocyte antigen C

MSI:

Microsatellite instability

iFOBT:

Immunochemical fecal occult blood testing

PD-1:

Programmed cell death receptor 1

PD-L1:

PD-1 ligand

HIF:

Hypoxia-inducible factor

STAT3:

Signal transducer and activator of transcription-3

PTEN:

Phosphatase and tensin homolog

OSCC:

Oral squamous cell carcinoma

EMT:

Epithelial to mesenchymal transition

CCND2:

Cyclin D2

Dnmts:

DNA methyltransferases

PTC:

Papillary thyroid carcinoma

iPSCS:

Induced pluripotent stem cells

HDAC:

Histone deacetylase

eNSC:

Embryonic neural stem cell

FFM:

Free fat mass

MDSC:

Myeloid-derived suppressor cell

P-GP:

P-glycoprotein

LOY:

Loss of the Y chromosome

EDY:

Extreme downregulation of Y chromosome

ICB:

Immune checkpoint blockade

CTLA-4:

Cytotoxic T lymphocyte antigen 4

TME:

Tumor microenvironment

TMB:

Tumor mutation burden

CYT:

Cytolytic activity

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Funding

This study was funded by Health Science and Technology Capacity improvement Project of Jilin Province (2022JC069) and Natural Science Foundation of Jilin Province (YDZJ202301ZYTS047, YDZJ202201ZYTS281, YDZJ202301ZYTS080).

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Authors and Affiliations

  1. The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China

    Huan Li, Manshi Yang, Siyuan Chen & Yihan Pan

  2. Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China

    Weibo Jiang

  3. Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China

    Shui Liu & Mengying Cui

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  1. Huan Li
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Contributions

MC conceptualized the review paper. HL structured the review. SL designed the Figures. HL & WJ contributed major amounts to manuscript writing. SC & MY & YP surveyed the literature. All authors were major contributors to revision, editing and proof-reading the manuscript. All authors read and approved the final manuscript.

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Correspondence to Mengying Cui.

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Li, H., Jiang, W., Liu, S. et al. Connecting the mechanisms of tumor sex differences with cancer therapy. Mol Cell Biochem 479, 213–231 (2024). https://doi.org/10.1007/s11010-023-04723-1

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