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Review

Cancer Metastasis Through the Lymphatics: Invasion and Dissemination

by
Chien-An A. Hu
*,
Christina Baum
and
Yahui Xie
Department of Biomedical Sciences, Kansas College of Osteopathic Medicine, Kansas Health Science University, Wichita, KA 67202, USA
*
Author to whom correspondence should be addressed.
Lymphatics 2025, 3(3), 17; https://doi.org/10.3390/lymphatics3030017
Submission received: 7 March 2025 / Revised: 12 June 2025 / Accepted: 18 June 2025 / Published: 24 June 2025
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Abstract

Cancer metastasis often accounts for the primary cause of cancer-related mortality, with the lymphatic system playing a pivotal role in the dissemination of malignant cells. While hematogenous vessel spread is commonly associated with distant organ metastasis, the lymphatic system serves as an early conduit for tumor cell invasion and dissemination. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, intravasation into lymphatic vessels, survival, transport, and colonization of regional lymph nodes (LNs). Cancerous cells then establish micro-metastases at the colonized sites and expand in the new microenvironment, ultimately resulting in the generation of secondary tumors. Tumor-secreted factors, such as vascular endothelial growth factors (VEGF-C and VEGF-D), contribute to metastasis through lymphangiogenesis, the formation of new lymphatic vessels. In addition, cancer cells utilize pre-existing chemokine signaling pathways by expressing chemokine receptors, such as CCR7, which bind to chemokine ligands, such as CCL19 and CCL21, to facilitate targeted migration into the lymphatic vessels. LNs are often the initial sites for metastasis and therefore are indicators of distant organ involvement. It is well established that the location and extent of LN involvement provides significant prognostic information, although the optimal treatment approach for LN metastases remains a subject of debate. Understanding the mechanisms of lymphatic metastasis offers potential therapeutic targets to mitigate cancer progression.

1. Cancer Metastasis Through the Lymphatics

Metastasis often accounts for the primary cause of cancer-related mortality. Malignant tumors, when confined and localized to their original site, are frequently less lethal and more amenable to curative treatments. The prognosis for patients with localized malignancies is generally favorable, especially with early detection and timely therapeutic interventions. Surgical intervention often serves as the primary treatment modality for localized cancers, aiming to excise the tumor entirely [1]. In contrast, metastatic cancer, the spread of cancer cells from the primary site to LNs and/or distant tissues of the body, creates a more complex clinical scenario. The prognosis for metastatic cancers is generally less favorable compared to localized forms, with varying survival rates depending on the cancer’s characteristics [1,2,3]. While hematogenous spread is commonly associated with distant organ metastasis, tumor cell migration and expansion in the lymphatics is sequential, metastasizing from proximal to distal LNs relative to the tumor. Lymphatic metastasis is a highly coordinated sequence of events that involves tumor invasion, intravasation into lymphatic vessels, transport, and colonization of regional LNs with ultimate systemic dissemination [4,5,6,7] (Figure 1). Understanding these mechanisms offers potential therapeutic targets to mitigate cancer progression and improve prognosis.

2. Role of the Lymphatic System

To elucidate the mechanisms by which the lymphatic system is exploited during cancer metastasis, it is essential to first understand its normal physiological functions. The lymphatic system constitutes the vascular component of the immune system and functions to collect interstitial fluid containing toxic metabolites, antigens, cellular debris, excess water, and other waste products extravasated from the blood and tissues throughout the body. This collected material is then transported from lymph to regional LNs for subsequent processing and immune surveillance [5,8]. The one-way valves transport the lymph drainage to the nearest LN where it is exposed to a microenvironment of the immune system. LNs house the B-cell follicle in the cortex, and the T-cell zone is in the paracortex. The medulla is the LN’s innermost portion and consists of blood vessels, sinuses, and a medullary cord with antibodies, macrophages, and additional B cells. Lymphocytes can enter LNs through the afferent vessels within the lymph or directly from the bloodstream through high endothelial venules (HEVs), specialized postcapillary venules that traffic lymphocytes into lymphoid organs. The totality of nearly 800 LNs is crucial for the body to safely eliminate waste without overwhelming the immune system. Lymphatic drainage in the body follows the general pattern of superficial to deep, proximal to distal, and caudad to cephalad until it reaches the thoracic duct. From the thoracic duct, the lymph then re-enters hematologic vasculature via the left venous angle. The inability to effectively neutralize and/or drain lymph leads to edema, cellular accumulation, decreased immune response, and hindered infection clearance [4,6,7,8]. When dysregulated, the lymphatic system is susceptible to disease processes such as the metastasis of various cancer types [9,10,11,12] (Figure 2). In a healthy individual, the LN’s immune cells adequately destroy the cancer cells being drained from the peripheral tissue. There are two key cancer cell-killing mechanisms: dendritic cells presenting cancer cell antigens to activate cytotoxic T cells and natural killer (NK) cells releasing perforin, granzymes, and cytokines (Figure 2A). In metastasis, cancer cells can promote the LN’s immune-suppressive state via upregulation of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and B-cell proliferation and inhibition of cytotoxic T cells and NK cells. The cancer cells can then implant in the LN and continue through the lymphatic circulation for further metastasis (Figure 2B).

3. Mechanisms of Lymphatic Metastasis

3.1. Tumor Cell Invasion

Tumor cells initiate metastasis by invading surrounding tissues by degrading extracellular matrix (ECM) components through proteolytic enzymes such as matrix metalloproteinases (MMPs) [10,11,12]. From the tissue, the tumor cells encounter the lymphatic vessels, which possess discontinuous basement membranes and loose intercellular junctions, rendering them highly permeable and accessible to migrating tumor cells [6]. Additionally, while soft/blood tumors or sarcomas often metastasize hematogenously, solid cancerous tumors or carcinomas typically metastasize via the lymphatic system [4,6,7,11]. Therefore, identifying the first LN that cancerous tissue drains into, the sentinel lymph node (SLN), and the tumor entity is crucial as it informs the location and prognosis of the cancer (Figure 1). The ordered drainage pattern provides insight into tumor aggression; tumor cell infiltration into an LN located distally from the primary tumor site suggests a more aggressive cancer phenotype.

3.2. Intravasation and Transport Through Lymphatic Vessels

Once tumor cells breach the basement membrane, they enter lymphatic vessels in a process known as intravasation. Unlike blood vessels, lymphatics lack continuous pericyte and smooth muscle coverage, facilitating passive tumor entry [7]. Lymphatic metastasis requires lymphotropic adaptations for successful surveillance evasion and lymphatic invasion. For example, healthy individuals’ dendritic cells and T cells migrate from the peripheral tissue to LNs utilizing the chemokine axis, such as C-C chemokine receptor 7 (CCR7), C-C chemokine ligand 19 (CCL19), and CCL21. The expression of CCL19 and CCL21 by HEVs and lymphatic endothelial capillaries (LECs) directs the recruitment of CCR7+ immune cells to the LNs [13,14] (Figure 2A). However, cancer cells can upregulate lymphangiogenesis, enhance LEC invasion, and modify the cellular immune defense by upregulating lymphangiogenic proteins, such as hypoxia-inducible factor 1-alpha (HIF1a) and platelet-derived growth factor (PDGF), to induce lymphangiogenesis and VEGF-C to destabilize the lymphatic vessels. They can also induce LECs to overexpress specific receptors, for example, lymphatic vessel endothelial hyaluronan receptor 1 [LYVE-1], vascular endothelial growth factor receptor 3 [VEGFR-3], and podoplanin [PDPN], to increase the lymphatic’s capacity to respond to the upregulated lymphangiogenic proteins [15] (Figure 3A). Furthermore, cancer cells can upregulate the expression of CCR7 and utilize the CCR7-CCL19/CCL21 axis for targeted recruitment and direct migration from peripheral tissue through LECs and into lymphatic circulation to achieve LN invasion (Figure 1 and Figure 3B). Moreover, cancer cells can modify various regulatory processes in the immune system. For example, cancer cells produce specific palmitoylated proteins that are secreted via tumor-specific exosomes to activate the transcription factor nuclear factor kappa-B (NF-kB) in tumor-associated macrophages, thereby increasing the secretion of pro-inflammatory cytokines. Continuous exposure to pro-inflammatory cytokines leads to a chronic immune state that promotes cancer growth [15,16,17]. Another example of tumor-induced immune regulation is aggressive breast cancer. When activated, the transcription factor estrogen receptor 1 (Esr1) in CD4+ T cells inhibits follicular T helper cells and subsequently suppresses the immune system, for example, functions of B cells, in SLNs [4,7,14,15] (Figure 3C). Cancer cells can then implant and establish a metastatic tumor within LNs, allowing them to travel efficiently to subsequent LNs, tissues, or organs [18]. In other words, a dysfunctional or remodeled lymphatic system serves as a highway for metastasizing cancer cells, with LNs being pit stops along the way. Chemokine/cytokine receptor–ligand interactions play a crucial role in altering the tumor microenvironment and guiding tumor cells toward lymphatic vessels, thereby increasing their metastatic potential [19]. Within the lymphatic circulation, tumor cells can either remain solitary or form embolic clusters that enhance their immune evasion and survival and resistance to shear stress [1,6,8].

3.3. Extravasation and Colonization of Regional Lymph Nodes

LNs serve as primary metastatic sites for tumor cell extravasation from lymphatic vessels and establish secondary growths. Subcapsular sinus macrophages (SSMs) within LNs can either eliminate invading tumor cells or promote their survival by modulating local immune responses [20,21,22]. The presence of tumor cells in SLNs often correlates with disease progression and serves as a prognostic indicator in various cancers [18]. LN metastases not only act as reservoirs for further systemic dissemination but also contribute to the establishment of pre-metastatic niches [9,22].

3.4. Systemic Dissemination via Lymphatics

The transition from regional LN metastases to systemic disease occurs through efferent lymphatic channels that ultimately drain into the bloodstream via the thoracic duct. This process enables tumor cells to escape the initial immune clearance and seed distant organs such as the lungs, liver, and bones [21]. Moreover, the LECs themselves may provide survival-promoting signals and microenvironment to metastatic cells, facilitating their further extravasation and systemic dissemination. For example, the chemokines CCL21 and CXCL12 released by activated LECs within SLNs might provide a niche for cancer cells with stem cell-like properties that express the receptors CCR7 and CXCR4 [5] (Figure 1 and Figure 3B).

4. Biomarkers for Diagnosis and Treatment of Lymphatic Metastasis

Biomarkers are a diverse group of molecules that can be used to detect, predict, and prognose the presence of metastasis. These include proteins, DNA polymorphisms, microRNAs, and other indicators that can be detected in lymphatics, blood, tissue, or other bodily fluids. The identification of biomarkers for lymphatic metastasis is crucial for early diagnosis, prognosis, and targeted therapy. The following is a breakdown of some key biomarkers and their roles.

4.1. Lymphangiogenesis Biomarkers

Lymphangiogenesis biomarkers facilitate cancerous tumor spread by promoting the growth of new lymphatic vessels. VEGF-C and VEGF-D are key pro-lymphangiogenic factors overexpressed by many tumors. VEGF-C and VEGF-D bind to vascular endothelial growth factor receptor-3 (VEGFR-3/FLT4), a tyrosine kinase receptor expressed on LECs [6]. Tumors overexpressing VEGF-C have higher rates of lymphatic spread, LN metastasis, and poor prognosis, particularly in breast and lung cancers. Thus, VEGF-C levels in serum can serve as a biomarker for lymphatic metastasis [11]. In addition, overexpression of VEGFR-3 in tumor-associated lymphatics enhances the metastatic spread of breast, colorectal, and prostate cancers. Targeting VEGFR-3 with inhibitors such as MAZ51 and SAR131675 has shown potential in preclinical cancer models [6,11] (Figure 1 and Table 1).

4.2. Tumor Cell Migration and Invasion Biomarkers

Prospero Homeobox Protein-1 (PROX-1), a master transcription factor involved in lymphatic development, regulates VEGFR-3 expression. Tumor cells expressing PROX-1 can undergo LEC-like differentiation, enhancing their capacity for lymphatic dissemination. PROX-1 has emerged as a diagnostic biomarker for lymphatic invasion in colorectal and hepatocellular carcinomas [20]. Additionally, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a glycoprotein expressed on LECs, facilitates tumor cell adhesion and migration into lymphatics. LYVE-1-positive lymphatic vessels act as entry points for metastatic cells, and increased LYVE-1 expression correlates with enhanced LN metastasis in melanoma and breast cancer, underscoring its potential as an imaging biomarker [4,15,20]. CCR7 expressed by tumor cells directs their migration towards lymphatic vessels expressing its ligand, CCL21. High CCR7 expression is strongly associated with LN metastasis in melanoma, gastric, and breast cancers [19]. MMPs, specifically MMP-2 and MMP-9, degrade extracellular matrix components, enabling tumor invasion into lymphatic vessels, and are notably elevated in LN-positive cancers [12]. Other molecules which include TWIST1, an EMT-inducing transcription factor that promotes tumor cell migration and metastasis, CXCR4, a chemokine receptor that mediates tumor cell migration to lymph nodes, fibronectin (FN1), a protein involved in cell adhesion and migration, potentially predicting lymph node metastasis, and microRNAs, small RNA molecules that can regulate gene expression and influence cancer cell behavior, have been shown to be promising in validating lymphatic metastasis [4,11,17].

4.3. Lymph Node Colonization Biomarkers

Podoplanin (PDPN), a glycoprotein prominently expressed on LECs and certain tumor cells, interacts with platelet receptor C-type lectin-like receptor 2 (CLEC-2) to facilitate tumor cell survival and metastasis. High PDPN expression is associated with increased lymphatic invasion and metastasis in head and neck squamous cell carcinoma and gliomas [21]. SSMs modulate the immune response to invading tumor cells within LNs. Their depletion has been shown to enhance lymphatic metastasis, suggesting a protective immunological role [22]. Interleukin-6 (IL-6), a pro-inflammatory cytokine, significantly promotes VEGF-C expression, tumor proliferation, and immunosuppression, and serves as a robust predictor of LN metastasis in colorectal, breast, and lung cancers. Consequently, IL-6 inhibitors, such as Tocilizumab, are currently under investigation as potential anti-metastatic therapeutic agents [15,22] (Table 1).

4.4. Systemic Dissemination Biomarkers

Systemic dissemination biomarkers significantly influence the capability of tumor cells to exit LNs and enter the systemic circulation. Biomarkers associated with epithelial–mesenchymal transition (EMT), including E-cadherin, N-cadherin, and vimentin, facilitate invasive tumor cell phenotypes, promoting migration through the lymphatic system. Decreased expression of E-cadherin and increased levels of N-cadherin and vimentin are indicative of elevated metastatic potential [9]. Forkhead Box C2 (FOXC2), involved in lymphatic development, enhances cancer cell plasticity during metastasis, with elevated FOXC2 expression correlating with aggressive phenotypes in breast cancer and melanoma [5].
Cancer stem cells (CSCs), characterized by self-renewal capability, genetic mutability, sustained tumor proliferation, and increased plasticity, significantly contribute to metastasis [4,9,15]. Among CSC biomarkers, CD133 (Prominin-1), a pentaspan transmembrane glycoprotein localized predominantly in cellular membrane protrusions [16,17,25], has been extensively studied. Initially identified in progenitor cell populations and adult tissues such as the mammary gland [26,29], CD133 plays critical roles in morphogenetic processes, including ductal branching and luminal–basal cell ratios [23]. CD133 influences tumor progression through promoting membrane organization and enhancing lymphatic and hematogenous metastasis, contributing to poor clinical outcomes in breast cancer [25,26,29] (Table 2). CD133-positive cells exhibit heightened colony formation efficiency, proliferation rates, and tumorigenic capabilities [30]. These cells also demonstrate enhanced self-renewal, prosurvival autophagy, stemness, invasiveness, chemoresistance, and metastatic potential [23,29,30,31,32,33].
CD133 promotes tumor growth by inducing lymphangiogenesis through VEGF-C, enhancing lymphatic invasion, and upregulating EMT-related biomarkers [19,22,27]. Its regulatory network involves stimulatory molecules (e.g., HIF, Notch, TGFβ, PI3K, IL-6, N-cadherin) [24,27,28,34,35,36,37,38,39] and inhibitory molecules (e.g., MALAT1, HuR, PLC-β2), which modulate its role in cancer progression [27,28,36,38] (Figure 4). CD133 expression correlates strongly with adverse prognostic indicators, including higher tumor grade, lymph node metastasis, negative hormone receptor (PR, ER) and HER2 statuses, advanced TNM stages, reduced overall survival, younger age at diagnosis, and premenopausal status [40,41,42,43,44,45,46]. Consequently, CD133 serves as both a critical biomarker of cancer stem cells and a powerful prognostic factor for malignant breast tumor progression. Therapeutically, anti-CD133 antibodies and CD133-specific CAR-T cell therapies are currently undergoing clinical evaluation as potential cancer treatments [27,38,47,48] (Table 2).

5. Conclusions

Cancer metastasis significantly influences disease progression and prognosis. Early identification of localized cancers frequently leads to curative outcomes and favorable prognoses. In contrast, metastatic cancers present considerable therapeutic challenges and are associated with diminished survival rates. Lymphatic metastasis typically involves a sequential process that includes tumor cell invasion into surrounding tissues, entry into lymphatic vessels, colonization of regional lymph nodes, and subsequent systemic dissemination, all of which are regulated by diverse molecular factors. A comprehensive understanding of the molecular and cellular dynamics governing these processes is critical for developing targeted therapeutic interventions capable of inhibiting distinct stages of invasion and dissemination, ultimately improving clinical outcomes.
Metastasis biomarkers serve dual roles as diagnostic and prognostic indicators and as therapeutic targets aimed at mitigating cancer progression. Targeted therapeutic approaches currently under investigation or development include blockade of VEGF-C/D and their receptor VEGFR-3 to inhibit lymphangiogenesis [11], antagonism of chemokine receptor CCR7 to disrupt chemokine-guided cellular migration [19], inhibition of MMPs to prevent ECM degradation [12], and employment of EMT-targeted drugs to curtail systemic tumor dissemination [9]. Additionally, immunomodulatory strategies designed to potentiate anti-tumor immune responses within LNs are actively being explored [4,11,15,20]. Further research aimed at elucidating the complex interactions between tumor cells and the lymphatic microenvironment is essential and holds promise for advancing novel diagnostic and therapeutic strategies.

Author Contributions

Conceptualization, C.-A.A.H., C.B. and Y.X.; methodology, C.-A.A.H., C.B. and Y.X.; validation, C.-A.A.H., C.B. and Y.X.; investigation, C.-A.A.H., C.B. and Y.X.; data curation, C.-A.A.H., C.B. and Y.X.; writing—original draft preparation, C.B. and Y.X.; writing—review and editing, C.-A.A.H., C.B. and Y.X.; visualization, C.-A.A.H., C.B. and Y.X.; supervision, C.-A.A.H.; project administration, C.-A.A.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

CCL, C-C chemokine ligand; CCR, C-C chemokine receptor; CLEC, C-type lectin-like receptor 2; CSCs, cancer stem cells; CXCL, CXC chemokine ligand; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; Esr1, estrogen receptor 1; LECs, lymphatic endothelial cells; MDSCs, myeloid-derived suppressor cells; MET, mesenchyme–epithelial transition; MMPs, matrix metalloproteinases; PDPN, podoplanin; SLN, sentinel lymph node; SSMs, subcapsular sinus macrophages.

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Figure 1. Schematic presentation of cancer metastasis through the lymphatics. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, dissemination, intravasation into lymphatic systems, survival, travel, extravasation, colonization of regional LNs, and formation of a secondary tumor. Specific regulators and biomarkers participating in each event have been identified and treated as therapeutic targets. See text for details.
Figure 1. Schematic presentation of cancer metastasis through the lymphatics. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, dissemination, intravasation into lymphatic systems, survival, travel, extravasation, colonization of regional LNs, and formation of a secondary tumor. Specific regulators and biomarkers participating in each event have been identified and treated as therapeutic targets. See text for details.
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Figure 2. Metastasis of cancer cells in lymph nodes. (A) In a healthy individual, the LN’s immune cells adequately destroy the cancer cells being drained from the peripheral tissue. Two key cancer cell-killing mechanisms are shown: dendritic cells presenting cancer cell antigens to activate cytotoxic T cells and natural killer (NK) cells releasing perforin, granzymes, and cytokines. (B) In successful metastasis, the cancer cells promote the LN’s immune-suppressive state via upregulation of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and B-cell proliferation and inhibition of cytotoxic T cells and NK cells. The cancer cells can then implant in the LN and continue through the lymphatic circulation for further metastasis.
Figure 2. Metastasis of cancer cells in lymph nodes. (A) In a healthy individual, the LN’s immune cells adequately destroy the cancer cells being drained from the peripheral tissue. Two key cancer cell-killing mechanisms are shown: dendritic cells presenting cancer cell antigens to activate cytotoxic T cells and natural killer (NK) cells releasing perforin, granzymes, and cytokines. (B) In successful metastasis, the cancer cells promote the LN’s immune-suppressive state via upregulation of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and B-cell proliferation and inhibition of cytotoxic T cells and NK cells. The cancer cells can then implant in the LN and continue through the lymphatic circulation for further metastasis.
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Figure 3. Cancer cell signaling pathways adapt to and remodel the lymphatic microenvironment, promoting metastasis. The combination of signaling modulations is unique to each type of cancer and can change throughout the tumorigenic progression. For example, upregulating lymphangiogenesis, enhancing LEC invasion, and modifying the cellular immune defense are well-known cancer modifications. (A) Cancer cells upregulate lymphangiogenic proteins, such as hypoxia-inducible factor 1-alpha (HIF1a) and platelet-derived growth factor (PDGF), to induce localized lymphangiogenesis and VEGF-C to destabilize the lymphatic vessels. They also upregulate LECs’ receptors (e.g., lymphatic vessel endothelial hyaluronan receptor 1 [LYVE-1], vascular endothelial growth factor receptor 3 [VEGFR-3], and podoplanin [PDPN]) to increase the lymphatic’s capacity to respond to the upregulated lymphangiogenic proteins. (B) Additionally, cancer cells express CCR7 and release VEGF-C. Utilizing the CCR7/CCL19-CCL21 and VEGF-C/VEGFR-3 axes promote direct migration of cells from peripheral tissue through LECs and into lymphatic circulation. (C) The tumor-induced modification of the immune system is a compilation of various enhancing and inhibiting processes. Palmitoylated proteins on tumor-secreted exosomes activate the transcription factor nuclear factor kappa-B (NF-kB) in tumor-associated macrophages, thereby increasing the secretion of pro-inflammatory cytokines. Continuous exposure to pro-inflammatory cytokines leads to a chronic immune state that promotes cancer growth. Another example of tumor-induced immune regulation is aggressive breast cancer. When activated, the transcription factor estrogen receptor 1 (Esr1) in CD4+ T cells inhibits follicular T helper cells and suppresses the immune system in SLNs.
Figure 3. Cancer cell signaling pathways adapt to and remodel the lymphatic microenvironment, promoting metastasis. The combination of signaling modulations is unique to each type of cancer and can change throughout the tumorigenic progression. For example, upregulating lymphangiogenesis, enhancing LEC invasion, and modifying the cellular immune defense are well-known cancer modifications. (A) Cancer cells upregulate lymphangiogenic proteins, such as hypoxia-inducible factor 1-alpha (HIF1a) and platelet-derived growth factor (PDGF), to induce localized lymphangiogenesis and VEGF-C to destabilize the lymphatic vessels. They also upregulate LECs’ receptors (e.g., lymphatic vessel endothelial hyaluronan receptor 1 [LYVE-1], vascular endothelial growth factor receptor 3 [VEGFR-3], and podoplanin [PDPN]) to increase the lymphatic’s capacity to respond to the upregulated lymphangiogenic proteins. (B) Additionally, cancer cells express CCR7 and release VEGF-C. Utilizing the CCR7/CCL19-CCL21 and VEGF-C/VEGFR-3 axes promote direct migration of cells from peripheral tissue through LECs and into lymphatic circulation. (C) The tumor-induced modification of the immune system is a compilation of various enhancing and inhibiting processes. Palmitoylated proteins on tumor-secreted exosomes activate the transcription factor nuclear factor kappa-B (NF-kB) in tumor-associated macrophages, thereby increasing the secretion of pro-inflammatory cytokines. Continuous exposure to pro-inflammatory cytokines leads to a chronic immune state that promotes cancer growth. Another example of tumor-induced immune regulation is aggressive breast cancer. When activated, the transcription factor estrogen receptor 1 (Esr1) in CD4+ T cells inhibits follicular T helper cells and suppresses the immune system in SLNs.
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Figure 4. The function and regulation of CD133 in breast cancer cell metastasis. CD133 contributes to cancer metastases through prosurvival autophagy, stemness and plasticity, tumor invasion, lymph node involvement, and epithelial–mesenchymal transition. Stimulators of CD133 include hypoxia, HIF, Notch, TGF, PI3K, and IL-6. Inhibitors include MALAT1, HuR, and PLC-β2.
Figure 4. The function and regulation of CD133 in breast cancer cell metastasis. CD133 contributes to cancer metastases through prosurvival autophagy, stemness and plasticity, tumor invasion, lymph node involvement, and epithelial–mesenchymal transition. Stimulators of CD133 include hypoxia, HIF, Notch, TGF, PI3K, and IL-6. Inhibitors include MALAT1, HuR, and PLC-β2.
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Table 1. Summary of representative biomarkers for lymphatic metastasis.
Table 1. Summary of representative biomarkers for lymphatic metastasis.
BiomarkerFunctionClinical SignificanceReferences
LYVE-1Lymphatic vessel receptorImaging biomarker for lymphatic metastasis[15,20]
VEGFR-3Lymphangiogenesis receptorTarget for VEGF-C/D inhibitors[6,11,23,24]
Podoplanin (PDPN)Lymphatic endothelial glycoproteinMarker for lymph node metastasis[15,21,22]
PROX-1Lymphatic differentiation factorDiagnostic marker for lymphatic invasion[20,21]
CD133Cancer stem cell markerTarget for CSC-directed therapies[23,25,26]
VEGF-CPro-lymphangiogenic factorPredicts aggressive lymphatic spread[6,11,22]
IL-6Inflammatory cytokineAssociated with VEGF-C-mediated metastasis[27,28]
Table 2. Functions of CD133 and representative associated molecules that CD133 regulates.
Table 2. Functions of CD133 and representative associated molecules that CD133 regulates.
FunctionMoleculesReferences
AutophagyHIF[34,35]
StemnessWnt signaling[36]
PI3K/Akt pathway[24,27,28]
Notch signaling[24,37]
InvasionTropomyosin-4 (Tm4)[27,28,38]
c-Met[27,28]
STAT 3[27,28]
MetastasisN-cadherin[39]
Lymph Node InvolvementTm4[27,28]
Epithelial–Mesenchymal
Transition		N-cadherin[39]
MALAT1[27,28]
HuR[27,28]
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Hu, C.-A.A.; Baum, C.; Xie, Y. Cancer Metastasis Through the Lymphatics: Invasion and Dissemination. Lymphatics 2025, 3, 17. https://doi.org/10.3390/lymphatics3030017

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Hu C-AA, Baum C, Xie Y. Cancer Metastasis Through the Lymphatics: Invasion and Dissemination. Lymphatics. 2025; 3(3):17. https://doi.org/10.3390/lymphatics3030017

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Hu, Chien-An A., Christina Baum, and Yahui Xie. 2025. "Cancer Metastasis Through the Lymphatics: Invasion and Dissemination" Lymphatics 3, no. 3: 17. https://doi.org/10.3390/lymphatics3030017

APA Style

Hu, C.-A. A., Baum, C., & Xie, Y. (2025). Cancer Metastasis Through the Lymphatics: Invasion and Dissemination. Lymphatics, 3(3), 17. https://doi.org/10.3390/lymphatics3030017

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