Impact of heparanase-2 (Hpa2) on cancer and inflammation: Advances and paradigms

Israel Vlodavsky, Maram Hilwi, Yasmin Kayal, Soaad Soboh, Neta Ilan

Research output: Contribution to journalReview articlepeer-review


HPSE2, the gene-encoding heparanase 2 (Hpa2), is mutated in urofacial syndrome (UFS), a rare autosomal recessive congenital disease attributed to peripheral neuropathy. Hpa2 lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase (Hpa1), yet it exhibits a high affinity toward HS, thereby inhibiting Hpa1 enzymatic activity. Hpa2 regulates selected genes that promote normal differentiation, tissue homeostasis, and endoplasmic reticulum (ER) stress, resulting in antitumor, antiangiogenic, and anti-inflammatory effects. Importantly, stress conditions induce the expression of Hpa2, thus establishing a feedback loop, where Hpa2 enhances ER stress which, in turn, induces Hpa2 expression. In most cases, cancer patients who retain high levels of Hpa2 survive longer than patients bearing Hpa2-low tumors. Experimentally, overexpression of Hpa2 attenuates the growth of tumor xenografts, whereas Hpa2 gene silencing results in aggressive tumors. Studies applying conditional Hpa2 knockout (cHpa2-KO) mice revealed an essential involvement of Hpa2 contributed by the host in protecting against cancer and inflammation. This was best reflected by the distorted morphology of the Hpa2-null pancreas, including massive infiltration of immune cells, acinar to adipocyte trans-differentiation, and acinar to ductal metaplasia. Moreover, orthotopic inoculation of pancreatic ductal adenocarcinoma (PDAC) cells into the pancreas of Hpa2-null vs. wild-type mice yielded tumors that were by far more aggressive. Likewise, intravenous inoculation of cancer cells into cHpa2-KO mice resulted in a dramatically increased lung colonization reflecting the involvement of Hpa2 in restricting the formation of a premetastatic niche. Elucidating Hpa2 structure–activity-relationships is expected to support the development of Hpa2-based therapies against cancer and inflammation.

Original languageEnglish
Article numbere23670
Pages (from-to)e23670
JournalFASEB Journal
Issue number10
StatePublished - 31 May 2024


  • ER stress
  • heparanase
  • heparanase-2
  • inflammation
  • metastatic niche
  • pancreatic cancer
  • protective effects
  • tissue homeostasis
  • tumor microenvironment
  • tumor suppressor
  • Neoplasms/pathology
  • Glucuronidase/metabolism
  • Humans
  • Inflammation/metabolism
  • Animals
  • Endoplasmic Reticulum Stress
  • Mice

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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