# SECRETED PHOSPHOPROTEINS ASSOCIATED WITH TUMORIGENICITY

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 1992 · $245,187

## Abstract

The broad long-term objectives of this project are to determine the
biological functions of secreted phospho-protein 1 (Sppl, also known as
osteopontin or 2ar). Elevated expression of this protein closely correlates
with tumorigenicity of rodent and human cells, and Sppl expression is
induced in mouse epidermis with tumor promoters. Identification of high
levels of Sppl in the serum of patients with disseminated carcinomas
provides evidence for a strong correlation between Sppl expression and
progressive tumor growth, and, moreover, provides direct evidence for an
association between elevated Sppl expression and human cancer.

Several findings suggest the hypothesis that Sppl promotes tumor cell
invasion; in particular, Sppl interferes with cell attachment to
extracellular matrix (ECM) and induces expression of the matrix degrading
protease, stromelysin (in zymogen form). The proposed experimental plan
will elucidate further the effects that Sppl exerts on tumor and host cells
that may facilitate tumor cell invasion and will determine the mechanisms
by which Sppl exerts these effects. The Specific Aims are: (1) determine if
Sppl binds to ECM components, if it prevents attachment to ECM components
in addition to vitronectin, and if it promotes tumor cell penetration of
ECM, (2) define the inductive effects of Sppl (native and thrombin-cleaved)
on synthesis of secreted proteases (especially stromelysin) by normal and
tumor cells, (3) characterize the cell surface receptors (presumably inte-
grins) which bind native and thrombin-cleaved Sppl, and (4) define the
distribution of Sppl and Sppl mRNA in human tumors with
immunohistochemistry and in situ hybridization and compare with the
distribution of stromelysin and stromelysin mRNA.

Binding of Sppl to ECM components and effects of Sppl on cell attachment to
ECM will be addressed with protein binding and cell attachment assays,
respectively. Effects of Sppl on tumor cell invasion will be assessed in
vitro by quantitating tumor cell penetration (in the presence and absence
of anti-Sppl antibodies) of ECM coated filters and amniotic membrane. The
inductive effects of thrombin-cleaved Sppl on normal and tumor cell
protease expression will be determined following addition of Sppl and/or
anti-Sppl antibodies. Expression of stromelysin and collagenases will be
quantitated with several techniques (immunoprecipitation, Northern
blotting, substrate assays).

Cell surface receptors (presumably integrins) for Sppl and thrombin-cleaved
Sppl will be identified with affinity chromatography and monoclonal
antibodies. These experiments will determine whether Sppl and
thrombin-cleaved Sppl mediate their different effects via the same or
different receptors and if they bind to vitronectin receptors. Finally,
detailed immunohistochemical studies on the distribution of Sppl in human
benign and malignant tumors, and in comparison with the distribution of
stromelysin, will be performed to determine the relationship of the...

## Key facts

- **NIH application ID:** 3171755
- **Project number:** 5R01CA034025-09
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **SAM.gov UEI:** C1CPANL3EWK4
- **Principal Investigator:** DONALD R SENGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $245,187
- **Award type:** 5
- **Project period:** 1983-03-01 → 1994-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3171755

## Citation

> US National Institutes of Health, RePORTER application 3171755, SECRETED PHOSPHOPROTEINS ASSOCIATED WITH TUMORIGENICITY (5R01CA034025-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3171755. Licensed CC0.

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