Elsevier

Mayo Clinic Proceedings

Volume 84, Issue 11, November 2009, Pages 985-1000
Mayo Clinic Proceedings

SPECIAL ARTICLE
Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents

https://doi.org/10.4065/84.11.985Get rights and content

Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents.

Section snippets

SHARED CHARACTERISTICS OF TROPHOBLAST CELLS AND TUMOR CELLS

Five days after fertilization, the human zygote forms into a structure consisting of 2 primary cell lines: the inner cellmass (or embryoblast) and the trophoblast.3 Trophoblast cells constitute the outer layer of the blastocyst, rapidly proliferating and invading the maternal endometrial decidua around day 7. A monolayer of cytotrophoblast cells surrounds the embryonic disc as the embryo completely embeds beneath the uterine decidua. By day 9, cytotrophoblast cells have differentiated into 2

PROLIFERATION

Like tumor cells, trophoblast cells have a very high proliferative capacity and exhibit molecular characteristics found in rapidly dividing cancer cells.54 For example, increased telomerase activity, typically not observed to a substantial degree in normal somatic cells, is detectable in 85% of human cancers.55 In fact, the intracellular concentration of telomerase is exponentially related to the proliferative capacity of a cell.56 In human pregnancy, telomerase activity is highest during the

INVASION

The sine qua non of both a successful pregnancy and the growth of cancer is the establishment of a blood and nutrient supply, and invasion through normal tissues is required for this process. However, whereas cancer cells spread throughout the host and then engage in local proliferation, trophoblasts follow an organized pattern of differentiation from proliferation to invasion without distant metastasis.72 Some of the molecular switches involved in this differentiation pattern and their

VASCULOGENIC MIMICRY

As trophoblasts invade maternal spiral arteries, they further differentiate to display a vascular phenotype in a process termed vasculogenic mimicry, in which cells other than endothelial cells form vascular structures.97 Vasculogenic mimicry can also be observed in aggressive cancers, and the genes and signaling pathways involved with the process of vasculogenic mimicry may be shared between EVT and cancer cells.98 For example, the matrix glycoprotein—binding galectin 3 is highly expressed in

ANGIOGENESIS

Molecular circuits involved in neoangiogenesis separate from vasculogenic mimicry are also likely shared between EVT and tumor cells. Angiopoietins and VEGF family members are extremely important in both spiral artery remodeling in placentation106 and the growth of many tumor types.107 Inhibition of VEGF has become an important therapeutic strategy in many cancers, although resistance can develop,108 resulting from the induction of an angiogenic rescue program characterized by the up-regulation

IMMUNOLOGIC PROPERTIES OF THE FETOMATERNAL INTERFACE AND TUMOR MICROENVIRONMENT

In addition to sharing many proliferative and invasive features, the cells of the trophoblast, like cancer cells, actively modulate the host immune response to develop and sustain a nutrient supply. Historically, the placenta was considered an inert, mechanical barrier protecting the semiallogeneic fetus from maternal immunologic attack.119 Current evidence, however, supports just the opposite—many maternal and placental immunomodulatory factors are required for adequate placental invasion.

EVIDENCE FOR SYSTEMIC IMMUNE MODULATION

Similar to the increasing antigenic burden of progressive cancer,214 fetal DNA can be found circulating in maternal blood by the second trimester in the height of the tolerogenic cytokine milieu.215 Although its immunologic consequences have not been fully elucidated, this circulating DNA likely contributes to tolerance and eventual exhaustion of antigen-specific CTLs. This phenomenon is well described for the human immunodeficiency virus, chronic infection with which leads to progressive

IMPLICATIONS FOR CANCER THERAPEUTICS

As a healthy pregnancy progresses toward parturition, several changes within the mother reflect a restoration of active, TH1-predominant immunity. Although Treg levels stay constant until the postpartum period,252 a gradual return of CD16+ NK cells is observed in late pregnancy.253 Suppressed earlier in pregnancy, circulating cytotoxic γδ-T cells increase with the onset of labor.254 Interleukin 2 levels decrease while granulocyte macrophage colony—stimulating factor and interferon-γ increase

CONCLUSION

By comparing immunologic patterns throughout healthy pregnancies, and in particular the return to TH1-polarized immunity through the third trimester, with those patterns observed in advanced malignancies, we have an opportunity to learn potential mechanisms to overcome the burden of long-term antigenic exposure and immunologic exhaustion in patients with cancer. The challenge for investigators in this field will be to extend our observations beyond the TH1/TH2 paradigm in both pregnancy and

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