Table 2 Molecular mechanisms and main signaling pathways of NSCLC lymphatic metastasis

Mdig

Inhibitor

HIF-1α/VEGF-C /VEGF-/D/VEGFR-3

A549, H1299, 293T, HUVECs, HLECs

-

Female athymic nu/nu mice

[52]

C/EBP-δ

Accelerator

HIF-1α/VEGF-C/VEGFR- 3

Human HMVEC-LLy, Lewis lung adenocarcinoma cells (3LL)

Migration, vascular network formation, and apoptosis of LECs

C57BL/6J mice and 

C/EBP-d-null mice

[53]

EFNA4

Accelerator

Ephrin A4

H1299, A549, PC9

Proliferation, migration, and adhesion

Male BALB/c nude mice

[57]

ANGPTL2

Accelerator

HIF-1/ VEGF-A

H1299, A549

-

-

[62]

ANGPTL2

Accelerator

integrin α5β1/ VEGF-A/p38/NF-κB

A549, CL1-0, CL1-5

Migration and tube formation of LECs

BALB/c nude mice

[63]

ANGPTL2

Accelerator

NF-κB/ TAMs M2 polarization

H1299, A549, HUVECs

Proliferation, invasion, and migration

LEC tube formation

BALB/c nude mice

[64]

NRP-2

Accelerator

TGF-β/VEGF-C/ HGF/c-MET/ GIPC1/PTEN

H358, A549

Migration, invasion, EMT, and EGFR resistance

NU/J (Foxn1nu/nu) mice

[55]

IGFBP7

Accelerator

-

LLC, L929

LEC tube formation

Female C57BL/6 mice and BALB/c nude mice

[74]

Shh signal pathway

Accelerator

Shh/ Gli1/LYVE-1

H1299, H2009, Calu-1

Proliferation

-

[76]

circTLCD4-RWDD3

Accelerator

UBC9/ SUMOylated hnRNPA2B1/ALIX/ESCRT-III/PROX1

A549, H1299

Migration and tube formation of HLECs

BALB/c nude mice

[83]

MiR-128

Inhibitor

VEGF-C/ VEGFR-3/ERK/AKT/p38

A549, SK-MES-1, NCI-H460, HUVECs

Proliferation, migration, invasion, apoptosis,  and angiogenesis

BALB/c nude mice

[85]

CXCR4

CCR7

Accelerator

VEGF-C/ VEGFR-2/VEGFR-3/ERK/p38/ AKT

A549

Proliferation and invasion

BALB/c nude mice

[88]

CCR7

Accelerator

VEGF-D/ERK/AKT

BE1, A549

-

-

[49]

CCR7-CCL21

Accelerator

TNF-α/NF-κB/VEGF-D

A549, H460

Invasion and metastasis

-

[90]

IL-7/IL-7R

Accelerator

c-Fos/c-Jun/VEGF-D

A549, SPC-A1, H460, LH7, SK-MES-1

Migration, invasion, and tumorsphere formation

-

[92]

IL-17

Accelerator

VEGF-C/ ERK

LLC, A549, SPC-A-1

Tube formation and chemotaxis of LECs

-

[93]

IL-1α

Accelerator

CXC chemokines/IKKb/NF-kB/VEGF-C

LNM35, N15, LLC/IL-1b

M2-like TAMs migration

Male KSN/slc mice

[95]

COX-2

Accelerator

PGE2/ VEGF-C/ EP1/4 receptors

Anip973, AGZY83-a

-

BALB/c nude mice

[96]

TSLP

Accelerator

LSP/IL-4/IL-13/VEGF-C

HLM, Monocyte, monocyte-derived macrophage

-

-

[99]

LEDGF

Accelerator

STRE/VEGF-C

A549, H1299

-

Female CD-1 nude mice

[100]

TGF-β1

Accelerator

VEGF-C

A549, NCI-H1993, NCI-H358

Proliferation, invasion, EMT, and CSCs

-

[118]

TGF-β1

Accelerator

-

H157, HMVEC-LLy

Adhesion and transmigration

Female athymic nude mice

[126]

CD147 methylation

Inhibitor

TGF-β/KLF6/MeCP2/DNMT3A/Sp1/Tet1/TDG/SMAD2/3

A549, NCI-H226, NCI-H460

Proliferation, invasion, and migration

Female BALB/c nude mice

[119]

Cathepsin

heparanase

Accelerator

VEGF-C /VEGFR-3

Macrophage, LLC, 4T1, A549, LM2-4

Migration, invasion, and paclitaxel resistance

-

[115]

miR-148a

Inhibitor

DNMT1/E-Cadherin/

A549, H1299

Migration and invasion

-

[122]

JAM-C

Accelerator

VEGF-C/β1 integrin/ERK

Anip973, AGZY83-a

Migration

BALB/c nude mice

[48]

p-S6

Accelerator

-

A549, SPC-A1

Migration and invasion

-

[127]

sVEGFR-2

Inhibitor

VEGF-C/VEGFR-2/VEGFR-3/MMP

LLC

-

C57BL/6 mice

[154]

EGFR-TKIs

Inhibitor

VEGF-C/VEGFR-2/ VEGFR-3/CCR7/JAK/STAT3/ c-Myc

HCC827, HLECs

Proliferation, migration, and lymphatic tube formation of LECs

Nude mice

[155]

Nintedanib

Inhibitor

VEGF-C

H1993

-

NOD/SCID mice

[156]

Anakinra

Inhibitor

IL-1α/VEGF-C

LNM35, N15, LLC/IL-1b

CXC chemokines and M2-like TAMs migration

Male KSN/slc mice

[95]

HN-N07

Inhibitor

BIRC5/HIF1A/FLT4

-

-

-

[157]

FR -sema3C

Inhibitor

VEGF-C/ERK/AKT

HUVECs, HLECs, LM2-4, HEK293

Collapse of the LECs Cytoskeleton

-

[159]

Itraconazole

Inhibitor

VEGF-C

Endothelial cell

MPE

-

[160]