1 INTRODUCTION
The brain, as the major organ of the
central nervous system (CNS),
controls and processes most of the body’s activities. Therefore, the
most malignant brain tumors,
namely, glioblastomas (GBMs) and
brain metastases (BrMs), from extracranial primary tumors (such as lung,
breast, melanoma, and colorectal cancers) are among the deadliest
cancers with poor prognosis and short survival [1].
At
present, an effective treatment option for patients with malignant brain
tumors has long presented a challenge for oncologists.
Gliomas
are one of the most prevalent tumors in the CNS with disproportionate
mortality and morbidity among subtypes. The most commonly occurring
types of gliomas are astrocytoma (WHO grade I - IV), oligodendroglioma
(WHO grade II - III), and GBM [2,
3].
Glioma
alterations, such as isocitrate
dehydrogenase (IDH ) 1 and 2 mutations as well as 1p/19qcodeletion, generally occur in low grade gliomas (II or III) and provide
superior prognostication compared to IDH wild-type tumors [4,
5].
Despite
routine therapies, such as surgical resection, radiation, and
chemotherapy, the outcomes of patients remain poor. The median survival
rates of glioma patients are stubbornly low, varying from years (WHO
grade II) to months (WHO grade IV)
[6].
BrMs
are 10 times more common than primary brain tumors with 10-30%
incidence in adults, and they have an even lower survival rate that is
typically measured in months
[7,
8].
Fewer
than 10% of all BrMs are found before the primary cancer is diagnosed.
The determination of whether extracranial tumors develop BrMs relies
mainly on cranial imaging
[magnetic resonance imaging
(MRI) or computed tomography (CT)], which has a severe time lag from
diagnosis to treatment, causing the optimal therapeutic timeframe to be
missed [9,
10].
In
addition, although these two representative primary and secondary brain
tumors exhibit markedly different modes of antigen presentation and
tumor microenvironment [11],
there
is no effective molecular marker to assist in distinguishing these two
types of brain tumors. The pathological diagnosis is confirmed by
immunohistochemistry from tumor tissue obtained after surgery or a
biopsy, which delays intervention and precise treatment selection.
Consequently, accurate preoperative discrimination of BrM and glioma is
critical for individualized therapeutic decision-making.
Markers
found in the blood and tissue samples have been utilized for the
diagnosis of the primary disease and to guide treatment. Recent studies
applying immunohistochemistry, genome-wide transcriptomics, and
single-cell transcriptomics to investigate BrMs and gliomas have had a
profound impact on cancer biology
[12-16].
Klemm
et al. constructed a high-dimensional, multi-omics characterization of
the brain tumor microenvironment, allowing elucidation of the disease-
and cell type-specific expression patterns of gliomas and BrMs [17].
However,
there are still challenges that hinder the transition of these findings
into new effective therapies. Potential explanations for the disconnect
between genomics-based studies and clinical trials include the lack of
protein information and the poor correlation between protein and mRNA
expression (0.54) [18, 19].
As
the main carrier and executor of life activities, protein shows a more
direct connection with the occurrence and development of diseases.
Despite some transcriptomic studies, the precise proteomic composition
of these two distinct human brain malignancies, especially BrMs, remains
unclear. Thus, an integrated and in-depth proteomic analysis is required
for the comprehensive understanding of these brain cancers.
Mass
spectrometry (MS)-based proteomics is an integral part of cancer
research, shedding light on the functional profile of the cancer cell.
The present study demonstrated for the first time a systematic proteomic
analysis of two typical malignant brain tumors, namely BrMs and gliomas.
We generated and analyzed a comprehensive catalog of the disease
type-specific protein expression patterns as a resource for the research
community, and we also investigated their
interrelationships.