p53, Estrogen, and NK Cells Shape Life and Cancer

There is a hidden symmetry between pregnancy and cancer.

In both, tissues must grow rapidly, blood vessels must expand into new territories, and the body must decide whether to permit or restrain invasion. What determines the difference between a nurturing womb and a growing tumor may lie in how a few molecular players — p53, estrogen receptors, natural killer (NK) cells, and VEGF/FLT1 — coordinate their dance around oxygen, stress, and the extracellular matrix.

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The Signal: p53 Meets Estrogen at the FLT1 Gene

In 2010, a PLOS ONE study by Ciribilli et al. uncovered a remarkable piece of the puzzle.
The researchers found that the FLT1 gene — which encodes VEGFR-1, a receptor that senses vascular growth factors — carries a tiny DNA variation (a promoter SNP) that can create a p53 response element. But here’s the twist: p53 doesn’t act alone. It activates FLT1 only when estrogen receptor α (ERα) is nearby, bound to its own DNA half-sites.

This means that p53, often called the guardian of the genome, cooperates with estrogen signaling to tune the sensitivity of blood vessels to VEGF and PlGF, the key drivers of angiogenesis. The study also showed that this activation happens after genotoxic stress such as doxorubicin, but not after other DNA-damaging agents like 5-fluorouracil, underscoring how specific the stress context must be.

In parallel, hypoxia — low oxygen levels — can activate the same FLT1 promoter through HIF-1α. Under these conditions, tissues produce not only the full receptor FLT1 but also its soluble form (sFlt-1), which soaks up VEGF and PlGF like a sponge. It’s a perfect tuning mechanism: too much sFlt-1, and angiogenesis is blocked; too little, and blood vessels grow unchecked.

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The Uterine Parallel: The Angiogenic Flood

A decade later, this molecular logic finds a physiological echo in early pregnancy. In The Angiogenic Growth Factor Flood, I explored how natural killer (NK) cells in the uterine lining (the decidua) create a surge of angiogenic growth factors just before and during implantation.

These decidual NK (dNK) cells express a2V-ATPase, acidifying the extracellular matrix and activating MMP-9, a powerful enzyme that cuts through collagen and releases growth factors bound within the ECM. The result is a literal flood of VEGF and PlGF — the same molecules p53 and ERα regulate through FLT1 expression.

Independent research confirms this choreography. During the first trimester, dNK cells secrete VEGF-C, PlGF, Angiopoietin-1/2, and MMP-2/-9, guiding spiral artery remodeling — the vital widening of maternal arteries that ensures proper blood flow to the placenta (Sojka et al., Frontiers in Immunology 2022). If this process falters, preeclampsia can develop, a condition marked by shallow invasion, high vascular resistance, and — notably — elevated sFlt-1 levels in maternal blood (Levine et al., NEJM 2004).

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Two Layers, One Circuit

Taken together, these findings reveal a single two-layered circuit:

1. The receptor layer –
   p53, ERα, and HIFs determine how much FLT1/sFlt-1 the tissue expresses, setting its sensitivity to VEGF and PlGF.

2. The matrix layer –
   NK cells and trophoblasts remodel the ECM via a2V-ATPase and MMP-9, controlling the availability of those same VEGF and PlGF molecules.

When these layers synchronize, arterial remodeling proceeds smoothly: arteries dilate, resistance drops, and the embryo receives life-sustaining flow. When they desynchronize, the results diverge — preeclampsia in pregnancy, or uncontrolled angiogenesis in tumors.

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From the Womb to the Tumor

It’s no coincidence that cancer co-opts the same program. Hypoxic tumor microenvironments stabilize HIF-1α and HIF-2α, driving VEGF and FLT1 expression much like the early placenta. Meanwhile, matrix metalloproteinases (MMPs) — especially MMP-9 — break down ECM barriers and unleash angiogenic factors, supporting invasion and metastasis. Some tumors even enlist NK-like cells that, paradoxically, promote angiogenesis rather than suppress it (Gao et al., Nature Reviews Immunology 2017).

The difference is control. In pregnancy, p53 remains intact but functionally moderated, allowing invasion to stop at the right depth. In cancer, p53 mutations or inactivation remove that restraint, unleashing angiogenesis without limit. Wild-type p53 can also induce thrombospondin-1, an anti-angiogenic protein, and repress VEGF itself (Teodoro et al., Nature Cell Biology 2006). When p53 is lost, that brake disappears.

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Lessons in Balance

The elegance of this system lies in its balance. The sFlt-1/PlGF ratio, now used clinically to predict preeclampsia, captures that equilibrium numerically (Zeisler et al., NEJM 2016). Too much soluble receptor, and the flood is dammed; too little, and angiogenesis runs wild.

The parallels between the placenta and the tumor remind us that biology reuses its best designs — sometimes for creation, sometimes for destruction. Both depend on oxygen gradients, immune-matrix crosstalk, and the nuanced cooperation of p53, ERα, HIFs, and NK-cell proteases.

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Looking Ahead

Understanding this unified circuit opens therapeutic possibilities on both fronts:

• In obstetrics, modulating the sFlt-1/PlGF balance and supporting healthy NK/trophoblast-matrix signaling may prevent or reverse preeclampsia.

• In oncology, restoring p53 function, adjusting ER context, or tempering HIF-driven FLT1 and MMP-9 activity could re-normalize tumor vasculature.

• In both, recognizing NK cells as angiogenic regulators — not just killers — reframes how immune therapy and vascular therapy intersect.

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Further Reading

• The Coordinated p53 and Estrogen Receptor Cis-Regulation at an FLT1 Promoter SNP — PLOS ONE (2010)

• The Angiogenic Growth Factor Flood — Codondex Blog (2022)

• Sojka et al., Front Immunol 2022 – Uterine NK cells and spiral artery remodeling

• Levine et al., NEJM 2004 – sFlt-1 and PlGF in preeclampsia

• Zeisler et al., NEJM 2016 – sFlt-1/PlGF ratio for preeclampsia prediction

• Teodoro et al., Nat Cell Biol 2006 – p53 repression of VEGF via thrombospondin-1

• Gao et al., Nat Rev Immunol 2017 – NK cells in angiogenesis and cancer

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p53 Direct Mechanisms In Immunity

Never in the field of molecular oncology have so many sites of posttranslational modification in one protein (p53) been modified by so many different enzymes, but direct response mechanisms that increase immune receptors are rarely discovered and have important implications.  

In the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) display an activated phenotype and can physically remodel the extracellular matrix (ECM). Silencing p53 in the CAFs strongly compromised this activity, implicating p53 as a key contributor to a distinctive CAF feature. Here, the non-autonomous, tumor-suppressive activity of non-mutant p53 cDNA is rewired to become a significant contributor to the CAFs’ tumor-supportive activities. This surprising role for p53 in CAFs suggests that, during tumor progression p53 functionality is altered, not only in the cancer cells, but also in their adjacent stroma.

Although p53 is not mutated in the human placenta, it has become functionally incompetent. Why and how p53 is functionally incompetent in cytotrophoblast cells might well be the key to understanding trophoblast invasion. Vascular remodeling for placentation is controlled by small populations of conventional Natural Killer cells, distinct from much larger populations of uterine NK cells, that acidify the ECM with a2V-ATPase, that activates MMP9, degrades the ECM and releases stored pro-angiogenesis growth factors. Similarly hypoxic TME's that in NK cells sustain excessive mitochondrial fission resulting in fragmentation could cause a2V-ATP activated MMP9 to similarly degrade ECM and promote angiogenesis in the early TME.  

Another MMP protein, MMP2 is a ligand for the Toll-like receptor 2 (Tlr2). Expression of Tlr2 and Tlr4 in the TME is important for the promotion of tumor growth, and when both of these receptors are absent, growth is compromised. Furthermore, the expression of Tlr2 and Tlr4 in both hematopoietic and stromal compartments appears to support MMP2-driven tumor growth.

The integration of the TLR gene family into the p53 regulatory network is unique to primates. p53 promoter response elements that are targeted by this DNA damage and stress-responsive regulator suggest a general p53 role in the control of human TLR gene expression. TLR genes show responses to DNA damage, and most are p53-mediated. TLR's mediate innate immunity to a wide variety of threats through recognition of conserved pathogen-associated molecular motifs. Expression of all TLR genes, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors with considerable inter-individual variability. Most TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites.

A polymorphism in a TLR8 response element provided the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings—demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress—have many implications for health and disease, as well as for understanding the evolution of DNA damage and p53 responsive networks. That p53 can directly increase an inflammatory response differs from the generally held view relating to the antagonistic affect of p53 on inflammation directed by NF-κB. However, the direct mechanism here is different in that it involves another p53-mediated increase in a receptor that translates ligand interactions into cytokine responses.

Angiogenic Growth Factor Flood

A previous series, about p53 culminated with "Blastocyst Development - A Perfected Cancer Model" that focused on the parallels in angiogenesis, triggered by blastocyst implantation and progression of tumors beyond ~1mm. Now, a recent study has found that conventional Natural Killer cells (cNK) control vascular remodeling in the uterus during pregnancy by acidifying the extracellular matrix (ECM) with a2V-ATPase that activates MMP-9 that degrades the ECM. Ablation of a2V-ATPase decreases Bax and p53 expression in testis and leads to implantation failure in the female mouse. The degrading ECM releases bound pro-angiogenic growth factors that contribute to Uterine artery (UtA) remodeling characterized by the loss of vascular smooth muscle cells (VSMCs) and dilation of the vessels. Without cNK, the UtA never lose VSMCs and UtA resistance remains high often leading to implantation failure.

Its logical that a timely flood of angiogenic growth factors, previously stored in the ECM would provide instant availability, but whether this explains the maternal-embryonic immune paradox remains to be determined? In the immune paradox maternal NK cells invade and maternal blood vessels are remodeled just before the arrival of trophoblasts, the external cells of the blastocyst, that carry male antigens during formation of the fetal placenta. A sudden flood of angiogenic factors preceding invading trophoblasts could provide the perfect environment required for maternal arterial/vascular remodeling.

Lymphocytes in the uterine lining (decidua) are dominated by a unique decidual natural killer (dNK) cell population. The dNK cell surface phenotype CD56bright CD16− CD3− and macrophages CD14+ CD206+(dMac) support a model whereby dNK cells, capable of killing extra-villous cytotrophoblasts (CTB), are prevented from doing so by neighboring macrophages thus protecting the fetal cells from NK cell attack. Existing research has centered on the function of the abundant and diverse sets of dNK, but now that cNK cells have been identified to play a more significant role, our understanding of the remodeling are likely to change.

In CTB exogenous p53 is able to down-regulate MMP-9 promoter activity, but endogenous p53 is not able to regulate MMP-9 expression in first trimester CTB cells. Inactivation of p53 through mutation is the most common trait in cancer. By loosing its onco-suppressive activity, p53 becomes oncogenic in almost all malignant tumors (Soussi and Lozano, 2005). Although p53 is not mutated in the human placenta, it has become functionally incompetent. Understanding why and how p53 is functionally incompetent in CTB might well be the key to understanding trophoblast invasion.

Downregulation of EMMPRIN (BSG,CD147) by p53 leads to a decrease in the activity of MMP-9 and an inhibition of tumor cell invasion. Upregulation of EMMPRIN seen in many cancers can be attributed to, at least in part, to the dysfunction of p53 and thus provides new evidence for the roles of p53 in tumor development and progression. Epithelial derived MMP-9 exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis. MMP-9 mediates Notch1 signaling via p53 to regulate apoptosis, cell cycle arrest, and inflammation. 

The inter-activity of p53, cNK and MMP-9 are complexed, but this novel research may lead to the mechanisms by which arterial remodeling occurs after release of angiogenic factors from ECM. If that shares characteristics of NK invasion into developing tumor micro environment's a new therapeutic approach may arise.